CN103772449B - C aryl glucoside derivatives and preparation method thereof and purposes - Google Patents

Abstract

The invention discloses a kind of formula（I）Shown C aryl glucoside derivatives, preparation method and the usage, wherein, R₁、R₂It is defined as in the description.Described C aryl glucosides derivant structure is novel, has very strong inhibitory activity to SGLT 2, while the selection ratio to SGLT 1 and SGLT 2 is also higher, available for the medicine for preparing treatment and prevention and sodium dependent glucose transport protein relevant disease.

Description

C- aryl glucoside derivatives and preparation method thereof and purposes

Technical field

The invention belongs to materia medica, pharmaceutical chemistry and area of pharmacology, more particularly to a kind of novel C-aryl glucose Glycoside derivates, the preparation method of such compound and its prepare treatment with sodium dependent glucose transport protein 2（sodium- Glucoseco-transporter 2, SGLT-2）Application in the medicine of relevant disease.

Background technology

Type ii diabetes are a kind of Non-Insulin Dependent Diabetes Mellitus, have sensitive organization to insulin replies failure and B Cell dysfunction and feature [the American Diabetes Association for causing hyperglycemia:Standards of medicalcare in diabetes2008.Diabetes Care,2008,31,Suppl 1,S12–S54].2010 11 Month, the newest investigation of diabetes mellitus in China association finds that for Chinese diabetes patient close to 100,000,000, surmounting India turns into diabetes first Big country, wherein more than 90% is type ii diabetes.

Currently used treatment diabetes medicament includes sulfonylurea, biguanides, insulin sensitizer（Row ketone）, non-sulphur Ureide derivative Drugs Promoting Insulin Secretion（Row how class）, alpha-glucosidase restrainer and list recently DPPIV inhibitor west he Arrange spit of fland etc..All these antidiabetic medicines are respectively provided with respective limitation：The common adverse reactions of sulfonylureas are stomach Acid secretes increase, nausea and other class OHAs is more easy to hypoglycemic reaction occurs, and biguanides main adverse reaction is Gastrointestinal reaction and lactic acidosis, insulin sensitizer are mainly hepatotoxicity wind agitation, and alpha-glucosidase restrainer can cause belly Flatulence and diarrhea, DPPIV inhibitor needs and melbine shares and can be only achieved preferable hypoglycemic effect.

The focus of international diabetes annual meeting in 2009 is 2 type sodium glucose transporters（SGLT-2）.Healthy human body is more than 99% By reuptaking blood back liquid after glomerular filtration, the blood glucose less than 1% is excreted in urine blood glucose, this process be by sodium according to Rely what property glucose transport body (SGLT-1/2) was completed.Wherein low-affinity, the SGLT-2 of high turn-over capacity, are mainly distributed on kidney It is dirty, complete 90% glucose in urine reabsorption [J.Med.Chem.2008,51,1145-1149].Now there are some researches show SGLT-2 inhibitor While hypoglycemic, do not put on weight, will not trigger hypoglycemia [Expert Opin.Pharmacother, 2009,10 (15), 2527-2535].And suppressing SGLT-2 can prevent glomerulus blood glucose from reuptaking, unnecessary blood glucose is set to drain in urine, so as to drop The blood glucose of low diabetes patient, alleviate the infringement under hyperglycemia state to target organ significantly.And high-affinity, low turn-over capacity SGLT-1 is mainly distributed on stomach, heart and kidney (completing 10% glucose in urine reabsorption), and suppressing SGLT-1 can cause heredity such as to integrate Levy serious negative consequence [Nature, 1991,350 (6316), the 354-356 such as glucose/galactolipin malabsorption (GGM); Biochim Biophys Acta,2001,1536,141-147]。

Hypoglycemic effect in compound body can be improved than not only by improving selection of the compound for SGLT1/SGLT2, and It is significant for drug safety.So we also need while how research improves SGLT-2 inhibitor activities Emphasis is wanted to consider to improve selection ratio of the compound for SGLT1/SGLT2.

SGLT-2 inhibitor has turned into current and has developed the most fruitful field of antidiabetic thing, many in the world Major company and institutions for academic research actively develop correlative study [Isaji M:Sodium-glucose cotransporter inhibitors for diabetes.Curr Opin Investig Drugs,2007,8,285–292；Current Opinion in I nvestigational Drugs,2007,8(4),285–292；Journal of Medicinal Chemistry,2009,52(7),1792-1794]。

The most fruitful work in the field at present is first that Bristol Myers Squibb and AstraZeneca are researched and developed jointly SGLT-2 inhibitor medicaments dapagliflozin.The medicine lists in March, 2012 in European Union.

During dapagliflozin has found, Mei-Shi Guibao's it was discovered by researchers that R on terminal phenyl rings when hundred Substituent selectively influences very big on SGLT-2 inhibitory activity, SGLT-1/SGLT-2, by screening different R groups, and combines Work in the past, Mei-Shi Guibao companies have found this candidate compound of dapagliflozin [Bioorg Med Chem when hundred Lett,2008,18,4770-4773;Journal of Medicinal Chemistry,2008,51,1145-1149]。

Different companies is all transformed the R substituent of this phenyl ring, also all achieves some good results [Pharmacol.Res.,2011,63,284-293；Bioorg.Med.Chem.Lett.,2009,19,5632-5635； Bioorg.Med.Chem.Lett.,2009,19,6877-6881.；J.Med.Chem.,2009,52,6201-6204.].It is different Experimental result show the change of R substituent, the improvement to compound activity and metabolic condition, there is vital influence.

Meanwhile Pfizer finds, by one oxygen bridge in the different head position of bglii fragment in dapagliflozin molecules and 5 increases Ring connects, SGLT-2 inhibitory activity, SGLT-1/SGLT-2 selectively all greatly improve [Bioorg.Med.Chem.Lett., 2010,20,1569-1572]。

Literature value：IC₅₀(h-SGLT2)=0.88nM

IC₅₀(h-SGLT1)=1960nM

The content of the invention

It is an object of the invention to provide one kind there is very strong inhibitory activity, fine SGLT-1/SGLT-2 to select to SGLT-2 Select than C- aryl glucosides derivative or its optical isomer, their Preparation method and use.

In the first aspect of the present invention, there is provided a kind of formula（I）Shown compound or its optical isomer：

Wherein：

R₂It is selected from：Hydrogen, chlorine or methyl；

Y is selected from：C=C or S；

R₁It is selected from：

Wherein, R₃It is selected from：Hydrogen, fluorine, chlorine, bromine, methyl or trifluoromethyl.

Multiple asymmetric carbon atoms be present in the compounds of this invention, therefore, compound shown in formula (I) include single enantiomer, Non-enantiomer mixture, racemic modification and single diastereomer.

Formula（I）Compound in, the title and structural formula of the preferable compound in part are as shown in table 1.

The representative compound of the present invention of table 1

In the second aspect of the present invention, there is provided the preparation method of the compounds of this invention.

The compound of the present invention can be prepared by following reaction process and description：

Flow 1：

As shown in flow 1, in polar aprotic solvent, the bromo- 2- chlorobenzoic acids of 5- are reduced with dimethyl sulphide borine etc. Agent reduces, and obtains intermediate a.

Intermediate a is at 0~-78 DEG C, in polar aprotic solvent, and in the presence of highly basic, with DMF（Dimethyl methyl Acid amides）Reaction obtains intermediate b；Polar aprotic solvent may be selected from：Toluene, dimethylbenzene, benzene, tetrahydrofuran, ether, methyl Tertiary butyl ether, Isosorbide-5-Nitrae-dioxane；Highly basic may be selected from：N-BuLi, isobutyl group lithium, tert-butyl lithium, trityl group lithium；Preferred stripe Part is：- 40 DEG C~-78 DEG C, using tetrahydrofuran as solvent, alkali is made with n-BuLi, reacts 1-3 hours.

At 0~60 DEG C, in polar aprotic solvent, under Louis acid catalysis, intermediate b and dithioglycol reaction Obtain intermediate c.Polar aprotic solvent may be selected from：Dichloromethane, chloroform, 1,2- dichloroethanes；Lewis acid may be selected from： Alchlor, zinc dichloride, BFEE, ferric trichloride, butter of tin, titanium tetrachloride；Optimum condition is：With dichloromethane Alkane is solvent, and BFEE is catalyst, reacts at room temperature 10-24 hours.

At 0~60 DEG C, in polar aprotic solvent, in the presence of base, pi-allyl halides and c react to obtain alkene The intermediate d of propyl group protection.Polar aprotic solvent may be selected from：DMF, dimethyl sulfoxide (DMSO) (DMSO), acetonitrile；Pi-allyl base halogen It may be selected from for thing：Allyl bromide, bromoallylene, allyl chloride；Alkali may be selected from：Sodium hydride, potassium carbonate, sodium carbonate, triethylamine, diisopropyl second Base amine；Optimum condition is：Using DMF as solvent, allyl bromide, bromoallylene and sodium hydride are added, reacts at room temperature 10-24 hours.

At 0~-90 DEG C, in polar aprotic solvent, in the presence of a strong base, intermediate d and e (its building-up process Referring to Journal of the Chemical Society, Perkin Transactions 1:Organic and Bio- Organic Chemistry(1972-1999),(1),21-6；1987) reaction obtains intermediate f.Polar aprotic solvent can It is selected from：Toluene, dimethylbenzene, benzene, tetrahydrofuran, ether, methyl tertiary butyl ether, Isosorbide-5-Nitrae-dioxane；Highly basic may be selected from：Normal-butyl Lithium, isobutyl group lithium, tert-butyl lithium, trityl group lithium；Optimum condition is：- 78 DEG C, using tetrahydrofuran as solvent, with normal-butyl Lithium makees alkali, reacts 1-5 hours.

At 0~90 DEG C, in polar aprotic solvent, intermediate f and fluorination reagent reaction, obtained after sloughing protection group Intermediate g.Polar aprotic solvent may be selected from：Tetrahydrofuran, ether, methyl tertiary butyl ether, Isosorbide-5-Nitrae-dioxane；Fluorination reagent It may be selected from：Tetra-n-butyl ammonium fluoride (TBAF), hydrofluoric acid pyridiniujm (PPHF)；Optimum condition is：Using tetrahydrofuran as solvent, add Enter tetra-n-butyl ammonium fluoride solution, react at room temperature 0.5-5 hours.

At 0~120 DEG C, in polar protic solvent, in the presence of base, intermediate g and formaldehyde react to obtain centre Body h.Polar protic solvent may be selected from：Methanol, ethanol and C₃-C₄Simple alcohols；Alkali may be selected from：Potassium carbonate, sodium carbonate, carbon Sour caesium, lithium carbonate；Optimum condition is：Using methanol as solvent, formaldehyde and potassium carbonate, 70 DEG C of -90 DEG C of reaction 10-30 hours are added.

At -20~60 DEG C, in polar aprotic solvent, intermediate i is generated with sodium borohydride reduction intermediate h.Should Reaction is complete in 0 DEG C of -30 DEG C of reaction 2-8 hour, reaction.In addition to sodium borohydride, other reducing agents can also be used, such as：Hydrogenation Lithium aluminium, sodium borohydride-BFEE, sodium borohydride-alchlor or sodium borohydride-titanium tetrachloride.

At 20~60 DEG C, using water as solvent, in the presence of Bronsted acid, intermediate i cyclizations obtain intermediate j.Bronsted acid It may be selected from：Trifluoracetic acid, acetic acid, formic acid；Optimum condition is：Substrate is dissolved in CF₃COOH:H₂O=9:1（Volume ratio）Solution in, Room temperature reaction 2-4 days.

At -20~60 DEG C, in polar aprotic solvent, in the presence of base, intermediate j and acetylation reagent are anti- Should, obtain full acetylated intermediate k.Polar aprotic solvent may be selected from：Dichloromethane, chloroform, 1,2- chloroethanes；Acetyl Change reagent may be selected from：Chloroacetic chloride, acetic anhydride；Organic base may be selected from：Triethylamine, diisopropyl ethyl amine (DIPEA), 4- diformazan ammonia Yl pyridines；Optimum condition is：Room temperature, alkali is made with DMAP, DIPEA, dichloromethane is solvent, Acetic anhydride is added, reacts at room temperature 10-20 hours.

At 20~120 DEG C, the in the mixed solvent of polar protic solvent and water, in the presence of base, intermediate k and palladium Reagent reacting, obtain intermediate l.Polar protic solvent is selected from：Acetic acid, trifluoracetic acid, formic acid；Palladium reagent may be selected from：Chlorination Palladium, palladium；Alkali may be selected from：Sodium acetate, sodium carbonate, potassium carbonate；Optimum condition is：Compound k is dissolved in glacial acetic acid:Water=9:1 （Volume ratio）Solution, add palladium chloride, sodium acetate, 60 DEG C -80 DEG C reaction 2-5h.

At 20~60 DEG C, in polar aprotic solvent, in the presence of brominated reagent, during intermediate l bromos obtain Mesosome m.Polar aprotic solvent is selected from：Dichloromethane, chloroform, 1,2- chloroethanes.Brominated reagent is selected from NBS- triphenylphosphines System, phosphorus tribromide.Optimum condition is：Compound l is dissolved in dichloromethane, adds NBS- triphenylphosphines, reacts at room temperature 2-6h.

Flow 2：

As shown in flow 2, at 20~160 DEG C, in polar aprotic solvent, bromide and palladium reagent, tin reagent Reaction obtains tin reagent intermediate.Polar aprotic solvent may be selected from：Toluene, dimethylbenzene, benzene, tetrahydrofuran, ether, methyl Tertiary butyl ether, Isosorbide-5-Nitrae-dioxane；Palladium reagent may be selected from tetra-triphenylphosphine palladium, the triphenylphosphine palladium triphenylphosphine system of dichloro two；Tin Reagent is selected from six normal-butyl tin ethers, tri-n-butyltin chloride.Optimum condition is that bromide is dissolved in into toluene, adds Pd (PPh₃)₄With Bu₃Sn-SnBu₃, 80 DEG C of -140 DEG C of reaction 5-15h.

Flow 3：

It is middle in the presence of alkali and palladium reagent in polar aprotic solvent at 20~160 DEG C as shown in flow 3 Stille coupling reactions occur for body iii and tin reagent intermediate, obtain coupled product.Polar aprotic solvent may be selected from：1, 4- dioxane, DMF (DMF), toluene, DMSO, glycol dimethyl ether (DME)；Alkali may be selected from：Potassium carbonate, Sodium carbonate, potassium phosphate, cesium carbonate.Palladium catalyst may be selected from：PdCl₂(PPh₃)₂-PPh₃, Pd (PPh₃)₄；Optimum condition is：With 1, 4- dioxane is solvent, and potassium carbonate makees alkali, Pd (PPh₃)₄For catalyst, 80-140 DEG C of reaction 5-15 hour.

At 0~100 DEG C, in polar protic solvent, in the presence of alkali, coupled product deprotection base, obtain Formula（I）Compound.Polar protic solvent may be selected from：Water-tetrahydrofuran, methanol, ethanol；Alkali may be selected from：Potassium carbonate, carbonic acid Sodium, sodium hydroxide, lithium hydroxide, sodium methoxide, caustic alcohol.Optimum condition is：Using methanol as solvent, sodium methoxide makees alkali, adjusts pH =11, react at room temperature 0.1-5 hours.

In the third aspect of the present invention, there is provided the purposes of any compound noted earlier, sugar is treated or prevented for preparing Urine disease, obesity and other and sodium dependent glucose transport protein (SGLT-2) relevant disease medicine.

Main advantages of the present invention are：Formula of the present invention（I）Shown C- aryl glucosides derivative or its optics Isomers is the SGLT-2 inhibitor of a kind of recruit's structure, and they have very strong inhibitory activity and excellent medicine to SGLT-2 Thing metabolisming property and good security, the glucose in urine discharge for animal have obvious facilitation, particularly suitable as SGLT-2 inhibitor is used to treat the disease related to SGLT-2 such as diabetes, obesity.

Embodiment

With reference to specific embodiment, the present invention is expanded on further.It should be appreciated that these embodiments are merely to illustrate this hair It is bright, rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to routine Condition, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise parts and percentages are parts by weight and weight hundred Divide ratio.

In all embodiments, thermometer does not correct；¹H-NMR is recorded with the NMRs of Varian Mercury 400, is changed Displacement study is represented with δ (ppm)；MS measure Shimadzu LC-MS-2020 mass spectrographs.It is 200-300 that separation silica gel is undeclared Mesh, the proportioning of eluent is volume ratio.

Embodiment 1 (1S, 2S, 3S, 4R, 5S) -5- (the chloro- 3- of 4- (4- (2,5- dihydrofuran -3- bases) benzyl) phenyl) -1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 1）Preparation

Step 1. synthesizes the bromo- 2- chlorobenzyl alcohols of 5-（Formula a）

The chloro- 5- bromobenzoic acids (4.0g, 0.0170mol) of 2- are dissolved in anhydrous tetrahydro furan (24ml), argon gas protection, 0 Dimethyl sulphide borine (8.7ml, 0.0849mol) is added dropwise at DEG C, is reacted at room temperature 5 hours afterwards, TLC（Thin-layer chromatography）Monitoring is extremely Reaction is complete, ice-water bath, and water is slowly added dropwise, ethyl acetate extraction, is spin-dried for, obtains 3.6g white solids, crude product direct plunges into down One step.

Step 2. synthesizes the chloro- 3- hydroxymethylbenzaldehydes of 4-（Formula b）

Under argon gas protection, compound a (2.2g, 0.01mol) is dissolved in 20ml THF（Tetrahydrofuran）In, be cooled to- 78 DEG C, n-BuLi (8ml, 0.02mol) is added dropwise, insulation reaction 1h, DMF (11.5ml, 0.15mol), insulation reaction 1h is added dropwise, TLC is monitored to reaction completely, and reaction is quenched with saturated ammonium chloride, is extracted with ethyl acetate, organic phase washed with water, saturated common salt Water washing, dry, filtering, be spin-dried for, column chromatography obtains white solid (716mg, 42%).LC-MS:193.0[M+Na]⁺。

Step 3. synthesizes (the chloro- 5- of 2- (1,3- sulphur -2- bases) phenyl) methanol（Formula c）

Compound b (710mg, 4.16mmol) is dissolved in 15ml DCM, 1,3- of addition dimercaptopropanes (1.3ml, 12.49mmol), BFEE (1.6ml, 12.49mmol), room temperature reaction are added dropwise under ice bath, LCMS is detected, and is used under ice bath 1N sodium hydroxides are adjusted to alkalescence, DCM（Dichloromethane）Extraction, organic phase washed with water, saturated common salt water washing, dry, filtering, It is spin-dried for, column chromatography obtains white solid (420mg, 40%).

¹H NMR (400MHz, CDCl₃):δ1.88-1.97(m,1H),1.98-2.20(m,1H),2.88-2.94(m,2H), 2.94-3.01(m,2H),4.77(s,2H),5.15(s,1H),7.12-7.19(m,1H),7.25-7.37(m,2H),7.1(m, 1H)。

Step 4. synthesizes (2- (3- propylene oxygen methyl) -4- chlorobenzenes) -1,3- dithians（Compound d）

Compound c (2.13g, 8.17mmol) is dissolved in 20ml THF, be added portionwise at 0 DEG C sodium hydride (390mg, 9.8mmol), 30min is reacted at room temperature, allyl bromide, bromoallylene (1ml, 12.2mmol) is added dropwise, reacts at room temperature 2h, TLC is monitored to having reacted Entirely, reaction solution is poured into frozen water, be extracted with ethyl acetate, organic phase washed with water, saturated common salt water washing, dried, filtering, It is spin-dried for, column chromatography obtains yellow liquid (1.67g, 68%).

¹H NMR(400MHz,CDCl₃):δ7.60-7.61(s,1H),7.26-7.36(m,2H),5.94-6.02(m,1H), 5.33-5.38(m,1H),5.13-5.26(m,1H),5.15(s,1H),5.59(s,2H),4.09-4.13(m,2H),3.02- 3.09(m,2H),2.88-2.93(m,2H),2.14-2.20(m,1H),1.82-1.98(m,1H)。

Step 5. synthesize (R)-(sulphur -2- bases of 2- (3- propylene oxygen methyl) -4- chlorphenyls -1,3- two)-(（3as,4R,6R, 6aS）- 6- (tert-butyldimethyl silyl)-O-) -2,2- dimethyl furans-[3,4-d] [1,3]-Er Evil -4- methanol（Formula f）

Under argon gas protection, compound d (12.22g, 40.6mmol) is dissolved in the anhydrous THF of 100ml, is cooled to -78 DEG C, Be added dropwise to n-BuLi (18ml, 46mmol), drop finishes, insulation reaction 1.5 hours, Ar protections, by compound e (12.3g, 40.6mmol) be dissolved in 100mlTHF, it is cooled to -78 DEG C, above-mentioned reaction solution is added thereto, insulation reaction 1 hour allows its nature - 20 DEG C are warming up to, TLC detects a small amount of raw material, adds saturated ammonium chloride solution under ice bath, adds water, EA（Ethyl acetate）Extraction, has Machine is mutually washed with water, saturated sodium-chloride successively, and anhydrous magnesium sulfate is dried, and filtering, is spin-dried for, is obtained pale yellow oil 25.4g (crude product), Direct plunge into and react in next step.

Step 6. synthesizes（3aS,4S,6R,6aS）- 6- (sulphur of (R) -2- (3- propylene oxygen methyl -4- chlorphenyls) -1,3- two - 2- yls)-methylol -2,2, dimethyl furan [3,4-d] [1,3]-Er Evil -4- alcohol（Compound g）

By above-mentioned steps 5 gained crude product (25.4g, 42.1mmol）It is dissolved in 200ml THF, is cooled to 0 DEG C, is added dropwise to four fourths Base ammonium fluoride trihydrate (TBAF.3H₂O, 26.6g, 84.2mmol) THF (200ml) solution, insulation reaction 15min, TLC Detection reaction is complete, adds saturated ammonium chloride solution, adds water, EA extractions, organic phase washed with water, saturated sodium-chloride are washed, anhydrous Magnesium sulfate is dried, and filtering, is spin-dried for, column chromatography, is obtained white blister powder (7g, 34%).

¹H NMR(400MHz,CDCl₃):δ 7.93-8.05 (m, 2H), 7.32-7.38 (d, 1H), 5.92-6.02 (m, 1H), 5.33-5.42(m,1H),5.24-5.27(m,1H),5.11(s,1H),4.71-4.74(d,1H),4.59-4.63(m,1H), 4.50-4.52(d,1H),4.40-4.42(m,3H),4.14-4.16(m,1H),3.70(s,1H),3.05-3.07(m,1H), 2.60-2.75(m,3H),1.85-1.98(m,2H),1.4(s,3H),1.3(s,3H)。

Step 7. synthesize (3aS, 4S, 6R, 6aS) -6- (sulphur of (R) -2- (3- propylene oxygen methyl -4- chlorphenyls) -1,3- two - 2- yls)-methylol -2,2, dimethyl furan [3,4-d] [1,3]-Er Evil -4- alcohol（Formula h）

Ar is protected, and compound g (7g, 14.3mmol) is dissolved in 200ml methanol, addition potassium carbonate (9.9g, 71.6mmol) in formaldehyde (37%, 48.5ml, 644mmol), overnight, TLC detection reactions are complete for 85 DEG C of reactions, under condition of ice bath, A small amount of methanol is added, pH to 7 is adjusted with 1NHCl, is spin-dried for, adds water, EA extractions, organic phase washed with water, saturated sodium-chloride are washed, nothing Water magnesium sulfate is dried, and filtering, is spin-dried for, column chromatography, is obtained white blister powder (4.43g, 60%).

¹H NMR(400MHz,CDCl₃):δ7.93-8.05(m,2H),7.32-7.38(d,1H),5.95-6.00(m,1H), 5.33-5.37(m,1H),5.23-5.27(m,1H),5.10(s,1H),4.83-4.86(d,1H),4.72-4.75(m,1H), 4.61-4.64(m,1H),4.51-4.59(m,1H),4.43-4.47(m,1H),4.25-4.42(m,1H),4.09-4.15(m, 2H),3.83-3.94(m,1H),3.73-3.83(m,1H),3.10-3.14(m,1H),2.60-2.77(m.3H),1.92-1.98 (m,2H),1.4(s,3H),1.3(s,3H)。

Step 8. synthesize (3aS, 4S, 6R, 6aS) -6- (sulphur of (R) -2- (3- propylene oxygen methyl -4- chlorphenyls) -1,3- two - 2- yls)-methylol -3a- methylol -2,2- dimethyl furans [3,4-d] [1,3]-Er Evil -4- alcohol（Formula i）

Starting compound h (4.43g, 8.53mmol) is dissolved in 40ml methanol, ice bath is cooled to 0 DEG C, and boron hydrogen is added portionwise Change sodium (0.323g, 8.53mmol), room temperature reaction, during it each hour add 1.0eq sodium borohydride.LC-MS is examined It is complete to survey reaction, adds saturated ammonium chloride solution, is spin-dried for, DCM extractions, organic phase washed with water, saturated sodium-chloride are washed, anhydrous sulphur Sour magnesium is dried, and filtering, is spin-dried for, is obtained white powder 5.38g.Crude product direct plunges into next step.

Step 9. synthesize (1R, 2R) -1- (sulphur -2- bases of 2- (3- propylene oxygen methyl -4- chlorphenyls) -1,3- two } -2- (5,5- Two (methylol) -2,2- dimethyl -1,3- Er Evil -4-) -1,2- ethylene glycol（Formula j）

Compound i (5.38g, 10.3mmol) is dissolved in 160ml CF₃COOH:H₂O=9:1（Volume ratio）Solution in, room Temperature reaction 4 days, LC-MS detection reactions are complete, and 1N NaOH are adjusted to alkalescence, EA extractions, organic phase washed with water, saturated sodium-chloride Wash, anhydrous sodium sulfate drying, filter, be spin-dried for, obtain pale yellow powder (2.39g, 62%), directly throw in next step.

Step 10. synthesizes (1S, 2S, 3S, 4R, 5S) -5- (3- propylene oxygen methyl -4- chlorphenyls) -1- methylols -6,8- two Oxa- ring [3,2,1] octane -2,3,4- triols（Formula k）

Compound j (2.37g, 6.36mmol) is dissolved in 30ml DCM, addition DMAP (DMAP, 39mg, 0.32mmol), DIPEA (DIPEA, 8.1ml, 46.43mmol), be added dropwise under ice bath acetic anhydride (4ml, 41.98mmol), 18h, TLC detection reactions are reacted at room temperature.Under ice bath plus water quenching is gone out reaction, is extracted with DCM, organic phase washing, full Washed with sodium chloride, anhydrous sodium sulfate drying, filter, be spin-dried for, column chromatography obtains yellow powder (986mg, 29%).

¹H NMR(400MHz,CDCl₃):δ7.65-7.70(m,1H),7.26-7.39(m,2H),5.93-6.03(m,1H), 5.51-5.52(m,1H),5.41-5.49(t,1H),5.32-5.37(m,1H),5.31(s,1H),5.22-5.25(m,1H), 4.58-4.59(d,2H),4.52-4.56(d,1H),4.43-4.45(d,1H),4.08-4.11(m,2H),3.94-3.97(d, 1H),3.70-3.71(dd,1H),2.09(s,3H),2.02(s,3H),2.00(s.3H),1.82(s,3H)。

Step 11. synthesizes (1R, 2S, 3S, 4R, 5S) -1- (acetyl-o-methyl) -5- (3- [- propylene oxygen methyl -4- chlorobenzenes Base] -6,8- dioxanes [3,2,1] octane) three base triacetates of -2,3,4-（Formula l）

By compound 4m (2.8g, 5.18mmol), palladium chloride (1.93g, 0.0109mol), sodium acetate (2g, 0.0246mol), glacial acetic acid:Water=9:1（Volume ratio）Solution (30ml) mixing, 70 DEG C reaction 3h, TLC detection, cooling reaction Liquid, filtering, filtrate add water, are extracted with ethyl acetate, and organic phase with saturated sodium bicarbonate, saturated common salt water washing, is dried successively, Filtering, rotation remove solvent, obtain yellow oil (2.05g, 80%).LC-MS:523.1[M+Na]⁺。

Step 12. synthesize (1R, 2S, 3S, 4R, 5S) -1- (acetoxy-methyl) -5- (4- chloro- 3- (methylol) phenyl) - The base triacetates of ring [3.2.1] octane of 6,8- dioxas two -2,3,4- three（Formula m）

Compound l (2.05g, 4.09mmol) is dissolved in 20ml dichloromethane, n- bromo succinyls are added under ice bath Imines (NBS, 0.875g, 4.91mmol), triphenylphosphine (1.3g, 4.91mmol) is added portionwise, overnight, TLC is examined for room temperature reaction Survey, be spin-dried for, column chromatography.Obtain yellow solid (1.315g, 57%).

¹H NMR(400MHz,CDCl₃) δ 7.59-7.60 (s, 1H), 7.39-7.40 (t, 2H), 5.9-5.51 (dd, 1H), 5.40-5.44(t,1H),5.28-5.30(d,1H),4.51-4.63(m,3H),4.44-4.46(d,1H),3.95-3.98(d, 1H),3.71-3.74(dd,1H),2.11(s,3H),2.04(s,3H),2.00(s,3H),1.83(s,3H).

Step 13. synthesizes the bromo- 4- isoolefines propylbenzenes of 1-（Formula 1-1）

To advance water removal except the three-necked bottle of air adds Ph₃PCH₂Br (29.6g, 82.9mmol), add part THF (130ml), t-BuOK (25.368g, 226.08mmol) is added portionwise in ice bath, reacts 1h, parabromoacetophenone is dissolved in surplus Reaction bulb, 75 °C of backflow reaction overnights are added in remaining 20ml THF.Next day, TLC is monitored to reaction completely, to reaction system In plus water quenching go out reaction, EA is extracted, organic phase saturated common salt water washing, anhydrous Na₂SO₄Dry, filtering, vacuum removes solvent, residual Thing is stayed to obtain transparency liquid (10.473g, 70.5%) through flash column chromatography (petroleum ether).LC-MS:219.0[M+Na]⁺。

Step 14. synthesizes 1- bromo- 4- (3- bromine isoolefines propyl group) benzene（Formula 1-2）

Ar protection under, by compound 1-1 (7.5g, 38.06mmol) and recrystallized n- NBSs (NBS, 10.2g, 57.09mmol) it is dissolved in 95ml CHCl₃In, it is heated to 75 °C of backflow reaction overnights.Next day, TLC are monitored to having reacted Quan Hou, insoluble matter, solvent evaporated are filtered out, then washed with petroleum ether, had white solid precipitation, filter out, filtrate is removed into solvent, directly Connect input in next step.

Step 15. synthesizes 1- (3- allyloxys-isoolefine propyl group) -4- bromobenzenes（Formula 1-3）

Sequentially added into dry three-necked bottle compound 1-2 (9.6g, 34.8mmol), 2- propylene -1- alcohol (3.03g, 52.2mmol) with THF (100m), the stirring reaction in ice bath, NaH (2.784g, 69.6mmol), room temperature mistake is then added portionwise Night reacts.Next day, TLC are monitored to reaction completely, flash column chromatography (petroleum ether:Ethyl acetate=50:1) yellow glue, is obtained Shape body (3.996g, 45%).LC-MS:275.0[M+Na]⁺。

Step 16. synthesis 3- (4- bromophenyls) -2,5- dihydros-tetrahydrofuran（Formula 1-4）

Under Ar protections, compound 1-3 (3.99g, 15.76mmol) and Grubbs II (267mg, 0.315mmol) are dissolved in 200ml CH₂Cl₂In, it is heated to 45 °C of back flow reactions and stays overnight.Next day, after TLC reactions completely, flash column chromatography (oil Ether:Ethyl acetate=50:1), vacuum removes solvent, obtains white solid (1.207g, 34%).

¹H NMR(400MHz,CDCl₃)δ：7.43(d,J=8.6Hz,2H),7.15(d,J=8.5Hz,2H),6.27-6.09 (m,1H),4.94(td,J=4.9,2.2Hz,2H),4.84-4.75(m,2H)。

Step 17. synthesizes 2- (4- tributyl tins phenyl) furans（Formula 1-5）

Compound 1-4 (500mg, 2.07mmol), Pd (PPh are added into the three-necked bottle being pre-dried₃)₄(159mg, 0.138mmol)、Bu₃Sn-SnBu₃(3.196g, 5.51mmol), toluene 15ml is steamed again, under argon gas protection in 100 DEG C of backflows overnight Reaction.Next day, after TLC reactions completely, remove solvent, rapid column chromatography（First use petroleum ether:Triethylamine=100:1 solvent and silicon In glue and post is rushed, then post, petroleum ether are rushed with 1.5L petroleum ethers：Ethyl acetate=50：1）, obtain product 157mg.Direct plunge into next Step.

Step 18. synthesize (1S, 2S, 3S, 4R, 5S) -1- (acetoxy-methyl) -5- (the chloro- 3- of 4- (2,5- dihydrofuran - 3- yls) benzyl) phenyl) two ring [3.2.1] octane -2,3,4- of -6,8- dioxas, three base triacetates（Formula 1-6）

Room temperature will be cooled to after the processing of three-necked bottle anhydrous and oxygen-free, under argon gas protection, by compound 1-5 (400mg, 0.709mmol), compound m (340mg, 0.78mmol), potassium carbonate (196mg, 1.418mmol), molecular sieve add 20ml toluene In, 30min is stirred at room temperature, adds four triphenyl phosphorus palladiums (82mg, 0.0709mmol), after back flow reaction is stayed overnight, adds silica gel to filter Reaction solution, it is spin-dried for, column chromatography, obtains white solid (140mg, 32%).LC-MS:623.2[M+Na]⁺。

Step 19. synthesizes (1S, 2S, 3S, 4R, 5S) -5- (the chloro- 3- of 4- (4- (2,5- dihydrofuran -3- bases) benzyl) benzene Base) -1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 1）

Compound 1-6 (70mg, 0.111mmol) is dissolved in pH=11 methanol solution of sodium methylate, reacted at room temperature 30min, TLC are detected, and are slowly added to acidic resins, regulation reaction solution to neutrality, are filtered, be spin-dried for, column chromatography, obtain white solid (22mg, 40%).LC-MS:483.2[M+Na]⁺。

¹H NMR(400MHz,CD₃OD)δ：7.47-7.48(d,J=1.8Hz,1H),7.35-7.41(m,2H),7.28- 7.30(d,J=7.2,2H),7.17-7.19(d,J=7.2,2H),6.27-6.28(m,1H),4.92-4.95(m,2H),4.77- 4.79(m,2H),4.13-4.14(m,1H),4.10(s,2H),3.81-3.84(m,1H),3.76-3.78(m,1H),3.62- 3.69(m,2H),3.53-3.59(m,2H)。

Embodiment 2 (1S, 2S, 3S, 4R, 5S) -5- (the chloro- 3- of 4- (4- (tetrahydrofuran -3- bases) benzyl) phenyl) -1- (hydroxyls Methyl) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 2）Preparation

With method prepare compound 2 similar to Example 1.Wherein, step 1-12 is the same as embodiment 1.

Step 13. synthesizes 2- (4- bromophenyls)-diethyl succinate（Formula 2-1）

Under argon gas protection, bromo-acid ethyl ester (6.08g, 0.025mol) will be dissolved in 60mlTHF, ice bath is cooled to 0 DEG C, potassium hexamethyldisilazide (KHMDS, 27.5ml, 0.0275mol) is added, bromoacetate is added after reacting 1h (2.8ml, 0.025mol), after reacting at room temperature 2h, TLC detections.Reaction is quenched with saturated ammonium chloride, ethyl acetate extraction is organic Mutually anhydrous sodium sulfate drying, filtering, it is spin-dried for water, saturated common salt water washing successively, column chromatography, obtains yellow oil (6.5g,79%)。

Step 14. synthesizes 2- (4- bromophenyls) -1,4 butanediols（Formula 2-2）

Compound 2-1 (340mg, 1.03mmol) is dissolved in THF (5ml, steaming) again, 0 DEG C is cooled to, is added portionwise NaBH₄(78mg, 2.07mmol), is then added dropwise BF again₃Et₂O (0.26ml, 2.07mmol).After adding, reaction 3h is warmed to room temperature. LCMS is detected, and reaction is complete, is cooled to 0 DEG C, is added 1NNaOH and is quenched, EA（Ethyl acetate）Extraction, aqueous phase extract two with EA again Time, merge organic phase, use brine（Saturated aqueous common salt）Water removal, anhydrous Na SO₄Dry 30min.Filtering, is spin-dried for, obtains yellow oil Shape thing (267mg, 100%).

¹H NMR(400MHz,CDCl₃)δ:7.44-7.46 (d, 2H), 7.10-7.12 (d, 2H), 4.74-4.76 (d, 2H), 3.66-3.72(m,1H),3.53-3.58(m,1H),2.92-2.96(m,1H),1.96-2.07(m,1H),1.81-1.88(m, 1H)。

Step 15. synthesizes 4- (4- bromophenyls) -3-1H- pyrans（Formula 2-3）

Compound 2-2 (230mg, 0.938mol) is dissolved in 5mlTHF, under ice bath add sodium hydride (38mg, 0.938mol), paratoluensulfonyl chloride (179mg, 0.938mol) is added after reacting 30min, hydrogenation is added after reacting at room temperature 1h Sodium (38mg, 0.938mol), react TLC detection reactions after 1h.Reaction solution is poured into frozen water, is extracted with ethyl acetate, with full And brine It, anhydrous sodium sulfate drying, filtering, it is spin-dried for, column chromatography, obtains yellow oil (70mg, 33%).

¹H NMR(400MHz,CDCl₃)δ:7.41-7.44 (d, 2H), 7.11-7.14 (d, 2H), 4.03-4.13 (m, 2H), 3.87-3.93(m,1H),3.67-3.71(m,1H),3.92-3.40(m,1H),2.32-2.45(m,1H),1.91-2.00(m, 1H)。

Step 16. synthesizes 2- (4- tributyl tins phenyl) furans（Formula 2-4）

Operation is with the step 17 in embodiment 1, except that the compound 2-3 added amount is 500mg （2.07mmol), product 178mg is obtained.

Step 17. synthesize (1S, 2S, 3S, 4R, 5S) -1- (acetoxy-methyl) -5- (the chloro- 3- of 4- (4- (tetrahydrofuran - 3- yls) benzyl) phenyl) two ring [3.2.1] octane -2,3,4- of -6,8- dioxas, three base triacetates（Formula 2-5）

Operation is with the step 18 in embodiment 1, except that the compound 2-4 added amount is 341mg （0.78mmol), white solid product (163mg, 42%) is obtained.LC-MS:653.2[M+Na]⁺。

Step 18. synthesizes (1S, 2S, 3S, 4R, 5S) -5- (the chloro- 3- of 4- (4- (tetrahydrofuran -3- bases) benzyl) phenyl) -1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 2）

Operation is with the step 19 in embodiment 1, except that the compound 2-5 added amount is 38mg （0.060mmol), final product white solid is obtained（18mg, 65%）.LC-MS:485.2[M+Na]⁺。

¹H NMR(400MHz,d6-DMSO)δ：7.48(d,J=1.8Hz,1H),7.43-7.31(m,2H),7.14(q,J= 8.3Hz,4H),4.14(d,J=7.5Hz,1H),4.10–4.04(m,3H),4.01(dd,J=8.3,4.5Hz,1H),3.92- 3.80(m,2H),3.77(d,J=8.3Hz,1H),3.70-3.61(m,3H),3.58(d,J=7.4Hz,1H),3.54(d,J= 7.9Hz,1H),3.42-3.33(m,1H),2.33(d,J=7.5Hz,1H),1.97(dd,J=12.3,8.2Hz,1H)。

Embodiment 3 (1S, 2S, 3S, 4R, 5S) -5- (the chloro- 3- of 4- (4- (3,6- dihydro -2H- pyrans -4- bases) benzyl) benzene Base) -1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 3）Preparation

With method prepare compound 3 similar to Example 1.Wherein, step 1-12 is the same as embodiment 1.

Step 13. synthesizes tributyl (4- (3,6- dihydro -2H- pyrans -4- bases) phenyl) stannane（Formula 3-2）

Operation is with the step 17 in embodiment 1, except that compound 3-1 dosage is 500mg（2.07mmol), Pd (PPh₃)₄Dosage be 120mg（0.104mmol), Bu₃Sn-SnBu₃Dosage be (2.41g, 4.15mmol).

Wherein, compound 3-1 preparation method is referring to United States Patent (USP) US2011092501.

Step 14. synthesize (1S, 2S, 3S, 4R, 5S) -1- (acetoxy-methyl) -5- (the chloro- 3- of 4- (4- (3,6- dihydros - 2H- pyrans -4- bases) benzyl) phenyl) two ring [3.2.1] octane -2,3,4- of -6,8- dioxas, three base triacetates（Formula 3-3）

Operation is with the step 18 in embodiment 1, except that compound 3-2 dosage is 350mg（0.78mmol), obtain To product as white solid (225mg, 45%).LC-MS:665.2[M+Na]⁺。

Step 15. synthesizes (1S, 2S, 3S, 4R, 5S) -5- (chloro- 3- of 4- (4- (3,6- dihydro -2H- pyrans -4- bases) benzyl) Phenyl) -1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 3）

Operation is with the step 19 in embodiment 1, except that compound 3-3 dosage is 22mg（0.060mmol), obtain To final product white solid（11mg, 70%）.LC-MS:497.2[M+Na]⁺。

¹H NMR(400MHz,CD₃OD)δ7.48(d,J=1.7Hz,1H),7.37(ddd,J=22.1,11.1,5.1Hz, 4H),7.15(d,J=8.1Hz,2H),6.12(d,J=2.9Hz,1H),4.27(d,J=2.7Hz,2H),4.21-3.98(m,3H), 3.97-3.71(m,4H),3.75-3.49(m,4H),2.48(d,J=1.8Hz,2H)。

Embodiment 4 (1S, 2S, 3S, 4R, 5S) -5- (the chloro- 3- of 4- (4- (tetrahydrofuran -2- bases) benzyl) phenyl) -1- (hydroxyls Methyl) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 4）Preparation

With method prepare compound 4 similar to Example 1.Wherein, step 1-12 is the same as embodiment 1.

Step 13. synthesizes 2- (4- tributyl tins phenyl) tetrahydrofuran（Formula 4-2）

Operation is with the step 17 in embodiment 1, except that compound 4-1 dosage is 617mg (2.76mmol), Pd (PPh₃)₄Dosage be 159mg（0.138mmol), Bu₃Sn-SnBu₃Dosage be 3.196g (5.51mmol), obtain product 124mg。

Wherein, compound 4-1 preparation method is referring to United States Patent (USP) US4868344.

Step 14. synthesize (1S, 2S, 3S, 4R, 5S) -1- (acetoxy-methyl) -5- (the chloro- 3- of 4- (4- (tetrahydrofuran - 2- yls) benzyl) phenyl) two ring [3.2.1] octane -2,3,4- of -6,8- dioxas, three base triacetates（Formula 4-3）

Operation is with the step 18 in embodiment 1, except that compound 4-2 dosage is 341mg（0.78mmol), obtain To product as white solid (177mg, 36%).LC-MS:655.2[M+Na]⁺。

Step 15. synthesizes (1S, 2S, 3S, 4R, 5S) -5- (the chloro- 3- of 4- (4- (tetrahydrofuran -2- bases) benzyl) phenyl) -1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 4）

Operation is with the step 19 in embodiment 1, except that compound 4-3 dosage is 21mg（0.060mmol), obtain Final product white solid（10mg, 63%）.LC-MS:485.2[M+Na]⁺。

¹H NMR(400MHz,CD₃OD)δ：7.34-7.51(m,3H),7.21-7.28(m,2H),7.14-7.16(d,1H), 6.97-6.98(d,1H),4.63-4.79(m,1H),4.02-4.17(m,3H),3.81-3.90(m,3H),3.52-3.69(m, 5H),2.26-2.32(m,1H),1.96-2.06(m,2H),1.70-1.82(m,1H)。

Embodiment 5 (1S, 2S, 3S, 4R, 5S) -5- (the chloro- 3- of 4- (4- (tetrahydrochysene -2H- pyrans -4- bases) benzyl) phenyl) -1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 5）Preparation

With method prepare compound 5 similar to Example 1.Wherein, step 1-12 is the same as embodiment 1.

Step 13. synthesizes tributyl (4- (tetrahydrochysene -2H- pyrans -4- bases) phenyl) stannane（Formula 5-2）

Operation is with the step 17 in embodiment 1, except that the compound 5-1 added amount is 990mg (4.10mmol), Pd (PPh₃)₄Amount be 237mg (0.205mmol), Bu₃Sn-SnBu₃Amount be（4.76g, 8.20mmol), Obtain product 400mg.

Wherein, compound 5-1 preparation method is referring to patent WO2006106416.

Step 14. synthesizes (1S, 2S, 3S, 4R, 5S) -1- (acetoxy-methyl) -5- (the chloro- 3- of 4- (4- (tetrahydrochysene -2H- pyrroles Mutter -4- bases) benzyl) phenyl) two ring [3.2.1] octane -2,3,4- of -6,8- dioxas, three base triacetates（Formula 5-3）

Operation is with the step 18 in embodiment 1, except that compound 5-2 dosage is 352mg（0.78mmol), obtain To product as white solid (116mg, 23%).LC-MS:667.2[M+Na]⁺。

Step 15. synthesizes (1S, 2S, 3S, 4R, 5S) -5- (the chloro- 3- of 4- (4- (tetrahydrochysene -2H- pyrans -4- bases) benzyl) benzene Base) -1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 5）

Operation is with the step 19 in embodiment 1, except that compound 5-3 dosage is 35mg（0.055mmol), obtain Final product white solid（17mg, 66%）.LC-MS:499.2[M+Na]⁺。

¹H NMR(400MHz,CD₃OD)δ7.48-7.49(d,1H),7.31-7.40(m,2H),7.14(s,4H),4.26- 4.27(d,1H),4.07-4.15(s,2H),3.99-4.03(m,2H),3.82-3.83(d,1H),3.76-3.78(d,1H), 3.63-3.67(m,2H),3.50-3.59(m,4H),2.69-2.76(m,1H),1.71-1.80(m,4H)。

Embodiment 6 (1S, 2S, 3S, 4R, 5S) -5- (the chloro- 3- of 4- (4- (ring -4- bases of 1,3- oxa-s six) benzyl) phenyl) -1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 6）Preparation

With method prepare compound 5 similar to Example 1.Wherein, step 1-12 is the same as embodiment 1.

Step 13. synthesizes 2- (4- tributyl tins phenyl) furans（Formula 6-2）

Operation is with the step 17 in embodiment 1, except that compound 6-1 dosage is 1g（4.15mmol), Pd (PPh₃)₄Dosage is 240mg（0.207mmol), Bu₃Sn-SnBu₃Dosage be 4.81g（8.29mmol), product 345mg is obtained.

Wherein, compound 6-1 preparation method is referring to document Synthesis, and 1980,11,871-872.

Step 14. synthesizes (1S, 2S, 3S, 4R, 5S) -1- (acetoxy-methyl) -5- (the chloro- 3- of 4- (4- (1,3- dioxas Six ring -4- bases) benzyl) phenyl) two ring [3.2.1] octane -2,3,4- of -6,8- dioxas, three base triacetates（Formula 6-3）

Operation is with the step 18 in embodiment 1, except that compound 6-2 dosage is 354mg（0.78mmol), obtain To product as white solid (120mg, 26%).LC-MS:669.2[M+Na]⁺。

Step 15. synthesizes (1S, 2S, 3S, 4R, 5S) -5- (chloro- 3- of 4- (4- (ring -4- bases of 1,3- dioxas six) benzyl) Base) -1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 6）

Operation is with the step 19 in embodiment 1, except that compound 6-3 dosage is 20mg（0.031mmol), obtain Final product white solid（8mg, 55%）.LC-MS:501.2[M+Na]⁺。

¹H NMR(400MHz,CD₃OD)δ7.50-7.51(d,1H),7.36-7.42(m,2H),7.10(s,4H),5.11 (s,1H),4.70-4.76(AB,2H),4.00-4.05(m,2H),3.82-3.83(d,1H),3.78-3.80(d,1H),3.65- 3.69(m,2H),3.52-3.61(m,4H),2.64-2.74(m,1H),1.70-1.78(m,4H)。

Embodiment 7 (1S, 2S, 3S, 4R, 5S) -5- (the chloro- 3- of 4- (4- (tetrahydrochysene -2H- pyrans -2- bases)) benzyl) phenyl) - 1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 7）Preparation

With method prepare compound 7 similar to Example 1.Wherein, step 1-12 is the same as embodiment 1.

Step 13. synthesizes 2- (4- tributyl tins phenyl) furans（Formula 7-2）

Operation is with the step 17 in embodiment 1, except that compound 7-1 dosage is 989mg（4.10mmol), Pd (PPh₃)₄Dosage be 237mg（0.205mmol), Bu₃Sn-SnBu₃Dosage be 4.76g（8.20mmol), product is obtained 576mg。

Wherein, compound 7-1 preparation method is referring to patent WO20060125526.

Step 14. synthesizes (1S, 2S, 3S, 4R, 5S) -1- (acetoxy-methyl) -5- (the chloro- 3- of 4- (4- (tetrahydrochysene -2H- pyrroles Mutter -2- bases)) benzyl) phenyl) two ring [3.2.1] octane -2,3,4- of -6,8- dioxas, three base triacetates（Formula 7-3）

Operation is with the step 18 in embodiment 1, except that compound 7-2 dosage is 354mg（0.78mmol), obtain To white solid (180mg, 39%).LC-MS:667.2[M+Na]⁺。

Step 15. synthesizes (1S, 2S, 3S, 4R, 5S) -5- (the chloro- 3- of 4- (4- (tetrahydrochysene -2H- pyrans -2- bases)) benzyl) benzene Base) -1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 7）

Operation is with the step 19 in embodiment 1, except that compound 7-3 dosage is 40mg（0.062mmol), obtain Final product white solid（17mg, 57%）.LC-MS:499.2[M+Na]⁺。

¹H NMR(400MHz,CD₃OD)δ：7.48-7.51(d,1H),7.33-7.39(m,2H),7.13(s,4H),5.20 (s,1H),3.68-3.71(m,2H),4.07-4.10(m,2H),3.78-3.81(d,1H),3.70-3.74(d,1H),3.55- 3.59(m,2H),3.46-3.49(m,4H),2.66-2.74(m,1H),1.69-1.83(m,6H)。

Embodiment 8 (1S, 2S, 3S, 4R, 5S) -5- (the chloro- 3- of 4- ((5- (4- fluorophenyls) thiophene -2- bases) methyl) phenyl) - 1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 8）Preparation

With method prepare compound 8 similar to Example 1.Wherein, step 1-12 is the same as embodiment 1.

Step 13. synthesizes 2- (4- tributyl tins phenyl) furans（Formula 8-2）

Operation is with the step 17 in embodiment 1, except that compound 8-1 (1.05mg, 4.10mmol), Pd (PPh₃)₄ (237mg,0.205mmol)、Bu₃Sn-SnBu₃(4.76g, 8.20mmol), obtain product 678mg.

Wherein, compound 8-1 preparation method is referring to patent WO2008128321.

Step 14. synthesizes (1S, 2S, 3S, 4R, 5S) -1- (acetoxy-methyl) -5- (the chloro- 3- of 4- ((5- (4- fluorophenyls) Thiophene -2- bases) methyl) phenyl) two ring [3.2.1] octane -2,3,4- of -6,8- dioxas, three base triacetates（Formula 8-3）

Operation is with the step 18 in embodiment 1, except that compound 8-2 dosage is 367mg（0.785mmol), Compound m dosage is 443mg（0.785mmol）, obtain product as white solid (291mg, 56%).LC-MS:683.1[M+Na ]⁺。

Step 15. synthesizes (1S, 2S, 3S, 4R, 5S) -5- (the chloro- 3- of 4- ((5- (4- fluorophenyls) thiophene -2- bases) methyl) benzene Base) -1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 8）

Operation is with the step 19 in embodiment 1, except that compound 8-3 dosage is 67mg（0.101mmol), obtain Final product white solid（30mg, 60%）.LC-MS:515.1[M+Na]⁺。

¹H NMR(400MHz,CD₃OD)δ7.61-7.51(m,3H),7.42(dt,J=14.5,5.2Hz,2H),7.15- 7.03(m,3H),6.79(d,J=3.6Hz,1H),4.28(s,2H),4.15(d,J=7.5Hz,1H),3.87-3.52(m,6H)。

Embodiment 9 (1S, 2S, 3S, 4R, 5S) -5- (chloro- 3- of 4- ((5- (4- trifluoromethyls) thiophene -2- bases) methyl) Phenyl) -1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 9）Preparation

With method prepare compound 9 similar to Example 1.Wherein, step 1-12 is the same as embodiment 1.

Step 13. synthesizes 2- (4- tributyl tins phenyl) furans（Formula 9-2）

Operation is with the step 17 in embodiment 1, except that compound 9-1 dosage is 1.26mg（4.10mmol), Pd(PPh₃)₄Dosage be 237mg（0.205mmol), Bu₃Sn-SnBu₃Dosage be 4.76g（8.20mmol), product is obtained 798mg。

Wherein, compound 9-1 preparation is referring to Organic Letters, 2005 (7), 5083-5085.

Step 14. synthesizes (1S, 2S, 3S, 4R, 5S) -1- (acetoxy-methyl) -5- (the chloro- 3- of 4- ((5- (4- fluoroforms Base phenyl) thiophene -2- bases) methyl) phenyl) two ring [3.2.1] octane -2,3,4- of -6,8- dioxas, three base triacetates（Formula 9- 3）

Operation is with the step 18 in embodiment 1, except that compound 9-2 dosage is 406mg（0.785mmol), Compound m dosage is 443mg（0.785mmol）, obtain product as white solid (190mg, 46%).LC-MS:733.1[M+Na ]⁺。

Step 15. synthesizes (1S, 2S, 3S, 4R, 5S) -5- (chloro- 3- of 4- ((5- (4- trifluoromethyls) thiophene -2- bases) Methyl) phenyl) -1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 9）

Operation is with the step 19 in embodiment 1, except that compound 9-3 dosage is 56mg（0.079mmol), obtain Final product white solid（28mg, 65%）.LC-MS:565.1[M+Na]⁺。

¹H NMR(400MHz,CD₃OD)δ：7.99-7.59(m,4H),7.53-7.36(m,3H),7.33-7.21(m,1H), 7.14-6.91(m,1H).4.30(s,2H),4.17(d,J=7.5Hz,1H),3.85-3.55(m,6H)。

Embodiment 10 (1S, 2S, 3S, 4R, 5S) -5- (the chloro- 3- of 4- ((5- (4- aminomethyl phenyls) thiophene -2- bases) methyl) benzene Base) -1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 10）Preparation

With method prepare compound 10 similar to Example 1.Wherein, step 1-12 is the same as embodiment 1.

Step 13. synthesizes 2- (4- tributyl tins phenyl) furans（Formula 10-2）

Operation is with the step 17 in embodiment 1, except that compound 10-1 dosage is 1.03mg（4.10mmol), Pd(PPh₃)₄Dosage be 237mg（0.205mmol), Bu₃Sn-SnBu₃Dosage be 4.76g（8.20mmol), product is obtained 675mg。

Wherein, compound 10-1 preparation method is referring to Bulletin of the Chemical Society of Japan,2009(82),555-562。

Step 14. synthesizes (1S, 2S, 3S, 4R, 5S) -1- (acetoxy-methyl) -5- (the chloro- 3- of 4- ((5- (4- methylbenzenes Base) thiophene -2- bases) methyl) phenyl) two ring [3.2.1] octane -2,3,4- of -6,8- dioxas, three base triacetates（Formula 10-3）

Operation is with the step 18 in embodiment 1, except that compound 10-2 dosage is 363mg（0.785mmol), Compound m dosage is 443mg（0.785mmol）, obtain product as white solid (262mg, 51%).LC-MS:679.1[M+Na ]⁺。

Step 15. synthesizes (1S, 2S, 3S, 4R, 5S) -5- (chloro- 3- of 4- ((5- (4- aminomethyl phenyls) thiophene -2- bases) methyl) Phenyl) -1- (methylol) -6,8- dioxas two ring [3.2.1] octane -2,3,4- triols（Compound 10）

Operation is with the step 19 in embodiment 1, except that compound 10-3 dosage is 66mg（0.10mmol), obtain Final product white solid（31mg, 63%）.LC-MS:511.1[M+Na]⁺。

¹H NMR(400MHz,CD₃OD):δ7.67(d,2H),7.24-7.49(m,4H),7.13-7.17(m,2H),7.14- 6.91(m,1H).4.30(s,2H),4.17(d,J=7.5Hz,1H),3.85-3.55(m,6H),2.26(s,3H)。

The above-claimed cpd of the present invention of embodiment 11 is for SGLT-2, SGLT-1 inhibitory activity and its selection ratio

More than 99% blood glucose by reuptaking blood back liquid after glomerular filtration, the blood glucose less than 1% is drained healthy human body Into urine, this process is by sodium dependent glucose transporter（SGLT1/2）Complete.High-affinity, low turn-over capacity SGLT1 is mainly distributed on stomach, heart and kidney（Complete 10% glucose in urine reabsorption）, and low-affinity, the SGLT2 of high turn-over capacity （Complete 90% glucose in urine reabsorption）, it is mainly distributed on kidney.Suppressing SGLT1 can cause such as hereditary syndrome glucose/galactolipin The serious negative consequences such as malabsorption (GGM), so improving selection of the compound for SGLT1/SGLT2 can improve than not only Hypoglycemic effect in compound body, and it is significant for drug safety.

Experimental method refer to document：J.Med.Chem.2008,51,1145-1149..

The inoculation expression mankind SGLT-2 or SGLT-1 CHOK1 cells to 24- holes analysis plates, analysis plates contain 10% tire ox Serum, 400 μ g/mL Geneticins, the F-12 nutrient chemical combination of 50 units/mL Benzylpenicillin sodium salts G and 50 μ g/mL streptomycin sulfates Thing, density are 400000 cells/wells.After 37 DEG C are cultivated 2 days in the humid air containing 5% CO2, with pH 7.4 point Analyse buffer solution (137mMNaCl, 5mM KCl, 1mM CaCl₂、1mM MgCl₂, 50mM 4- hydroxyethyl piperazineethanesulfonic acids and 20mM tri- Hydroxymethyl aminomethane) washing cell contain experimental compound once, then with 250 μ L（The SGLT-2 that i.e. prepared by the various embodiments described above Inhibitor）Buffer solution, cultivated 10 minutes at 37 DEG C.Experimental compound is dissolved in DMSO.DMSO ultimate density is 0.5%.Start transhipment reaction by adding 50 μ L [14C]-methyl-α-D- glucopyranosides (14C-AMG) solution.In 37 DEG C After 2 hours of lower culture, culture mix is separated out, with cold PBS（Phosphate buffer）Cell washs 3 times.Then with 0.3N NaOH dissolves cell, and takes equal portions cell to utilize liquid flashing counter measuring radioactivity.Non-specific AMG absorbabilities definition For the absorbability in the presence of 100 μM of phloridzins (for sodium dependent glucose transport protein specific inhibitor).Pass through Protein concentration correction selectivity absorbability measured by Bradford methods.50% inhibition concentration (IC₅₀) value is bent by dose response Line is calculated using least squares method.

Experimental result：The biological activity test of representative compound of the present invention the results are shown in Table 2,3.

Table 2：The compound of the present invention is to SGLT-2 inhibitory activity

The compounds of this invention has stronger inhibitory activity for SGLT-2 in vitro as can be seen from Table 2, all better than upper City medicine Dapagliflozin (BMS comparison medicines), shows that the compounds of this invention has excellent activity.Especially compound 1, its External activity is significantly due to Dapagliflozin.

Table 3：The compound selection ratio of the present invention（SGLT1 activity/SGLT2 activity）

The compounds of this invention SGLT1/SGLT2 selects ratio better than marketed drug Dapagliflozin as can be seen from Table 3 (BMS comparison medicines) and Pfizer's comparison medicine, especially compound 3, in the case where keeping preferably activity（Activity and Dapagliflozin is suitable）, select ratio to be significantly better than Pfizer's comparison medicine.And compound 1, keeping and Pfizer's comparison medicine activity In the case of quite, ratio is selected also superior to Pfizer's comparison medicine.Due to suppress SGLT-1 can cause as hereditary syndrome glucose/ The serious negative consequences such as galactolipin malabsorption (GGM), therefore, selection ratio of the compound for SGLT1/SGLT2 is improved, for It is significant to improve hypoglycemic effect and drug safety in compound body.

Metabolism in the normal rat body of 12 compound of embodiment 8

Experimental method：

Healthy SD rat 4, male, body weight 200-220g, gavage are given compound 8, dosage 20mg/kg, given Medicine body product is 10ml/kg；Fasting 12h before experiment, free water.2h is unified after administration feeds.Medicine is prepared with 0.5%CMC-Na Into suspension.0.25,0.5,1.0,2.0,3.0,4.0,5.0,7.0,9.0 and 24h takes through rat eye rear vein beard after administration Venous blood 0.3ml, puts in heparinised tubes, 3000rpm centrifugation 10min, separated plasma, is freezed in -20 °C of refrigerators.With LC/MS methods determine the plasma concentration of each sample point.Experimental result is as shown in table 4 below.

Table 4：Compound 8 is for metabolite data table in normal rat body

The compounds of this invention 8 has good Pharmacokinetics in Rat parameter as can be seen from Table 4：Inside longer Drug exposure (46043ng*h/mL) inside half-life period (8.86h) and ideal.It is obvious to show that the compounds of this invention has Quasi-medicated property, suitable for treating or preventing the disease related to SGLT-2, such as diabetes, obesity etc..

The rat urine glucose Emission test of embodiment 13

Rat urine glucose discharge capacity and concentration are determined, is that one of inspection SGLT2 inhibitor hypoglycemic validity is important Index.

Take qualified healthy male rat of quarantining（180~220g of body weight）30,5 groups are randomly divided into, every group 6, is distinguished For solvent control group, compound group, after each group Rat Fast 12h, gastric infusion, dosage 10mg/kg, administration respectively is held Product is 1.0mL/100g, and rat is put into metabolic cage after administration, determines urine volume and urine sugar value in 24h, measurement result such as table 5 It is shown.

The influence that 5 representative compound of the present invention of table is discharged to normal rat urine glucose

Compound

Urine volume (mL)

Urine sugar concentrations (μ g/dL)

Twenty-four-hour urine sugar (mg)

Solvent control group	16.3±2.4	107.3±24.6	17.2±2.2
				Compound 3	38.2±6.3	3232±385	1241±292**
Compound 4	23.3±6.1	4225.0±1165.1	940.3±147.3**
				Compound 5	30.5±11.0	2666.3±1139.8	727.3±206.2**
Compound 8	33.3±6.1	4126.0±835.1	1373.9±128.1**

**：Compared with solvent control group, there is significant difference（p<0.01）

As can be seen from Table 5：Compared with solvent control group, the compounds of this invention has obvious for the urine of normal rat Rush glucose discharge effect, especially compound 8 is respectively 4126.0 for urinate concentration and glucose in urine total amount of Rat 24 h ± 835.1 μ g/dL and 1373.9 ± 128.1mg are high 37 times and 78 times compared with solvent control group respectively.Further demonstrate that the present invention Compound has hypoglycemic activity inside obvious.

Summarize：From table 2,3,4,5 as can be seen that the present inventor completes a series of external activity experiment to compounds, External selection is than measure, internal metabolism and glucose in urine experiment.Good experimental result can be seen that we have found it is a series of There is very strong inhibitory activity to SGLT-2, while the selection ratio to SGLT-1 and SGLT-2 is also higher, is treated available for preparing With prevention and the compound of sodium dependent glucose transport protein relevant disease.

Claims (9)

1. compound or its optical isomer shown in a kind of logical formula (I)：

Wherein：

R₂It is selected from：Hydrogen, chlorine or methyl；

Y is selected from：C=C or S；

R₁It is selected from：

2. compound according to claim 1, it is characterised in that the R₂For chlorine.

3. compound according to claim 2, it is characterised in that the Y is C=C, the R₁It is selected from：

4. compound according to claim 3, it is characterised in that the compound is：

5. the purposes of the logical formula (I) compound any one of claim 1-4, it is characterised in that for prepare treatment or The medicine of the prevention disease related to sodium dependent glucose transport protein 2.

6. purposes according to claim 5, it is characterised in that described related to sodium dependent glucose transport protein 2 Disease includes diabetes, the complication of diabetes and obesity.

7. lead to the preparation method of formula (I) compound described in claim 1, it is characterised in that comprise the following steps：

1) at 20~160 DEG C, in polar aprotic solvent, under alkali and palladium catalyst effect, formula III compound and formula II tin Coupling reaction occurs for reagent, obtains formula IV compound：

2) at 0~100 DEG C, in polar protic solvent, in the presence of alkali, formula IV compound removing acetate, formula (I) is obtained Compound：

Wherein, R₁It is selected from：

R₂It is selected from：Hydrogen, chlorine or methyl；

Y is selected from：C=C or S.

8. according to the method for claim 7, it is characterised in that the reaction condition of step 1) is as follows：Solvent is 1,4- dioxies Six rings, alkali are potassium carbonate, and palladium catalyst is Pd (PPh₃)₄, reaction temperature is 80-140 DEG C, and the reaction time is 5-15 hours.

9. according to the method for claim 7, it is characterised in that the reaction condition of step 2) is as follows：Solvent is methanol, and alkali is Sodium methoxide, pH value of solution 11, reaction temperature are room temperature, and the reaction time is 0.1-5 hours.