CN104327027A - New C-aryl glycosidase SGLT2 (sodium glucose transporter type-2) inhibitor - Google Patents

New C-aryl glycosidase SGLT2 (sodium glucose transporter type-2) inhibitor Download PDF

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CN104327027A
CN104327027A CN201410548765.9A CN201410548765A CN104327027A CN 104327027 A CN104327027 A CN 104327027A CN 201410548765 A CN201410548765 A CN 201410548765A CN 104327027 A CN104327027 A CN 104327027A
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chloro
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benzene
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CN104327027B (en
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黄文龙
钱海
李政
王学堃
焦磊
邱倩倩
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China Pharmaceutical University
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings

Abstract

The invention discloses a new C-aryl glycosidase SGLT2 (sodium glucose transporter type-2) inhibitor, relates to the field of medicines associated with diabetes, and in particular relates to a new C-aryl glycosidase derivative shown as the general formula (I), a preparation method thereof, compositions thereof, and use thereof in preparing hypoglycemic drugs. The C-aryl glucoside derivative has excellent effect of promoting urine discharge and in-vivo hypoglycemic activity, and compounds with equal or better in-vivo hypoglycemic activity than that of dapagliflozin are screened out, and can be used for the prevention or treatment of diabetes.

Description

One class novel C-aryl glucoside SGLT2 inhibitor
Technical field
The present invention relates to the field of pharmacology relevant to diabetes, be specifically related to novel 2 type sodium-glucose transporter (SGLT2) inhibitor containing polyaryl glucoside structure of the medicative class of diabetes, the invention also discloses its preparation method, with the pharmaceutical composition that this compounds is activeconstituents, and they are preparing the application in hypoglycemic drug.
Background technology
Current global diabetic subject nearly 3.7 hundred million, wherein great majority are 2 types (i.e. non-insulin-depending type) diabetic subject.The medicine of traditional treatment diabetes mainly contains insulin type, N1,N1-Dimethylbiguanide class, sulfonylurea, thiazolidinediones and alpha-glucosidase inhibitor, and the medicine of the treatment diabetes of new listing has glucagon-like-peptide-1 (GLP-1) agonist, dipeptidyl peptidase-IV (DPP-IV) inhibitor etc. in recent years.These medicines have good therapeutic action, but long-term treatment diabetes exist safety issue, as: the problems such as the increase of liver toxicity, body weight and hypoglycemia.
2 type sodium-glucose transporter (SGLT2) are the novel targets that can be used to develop hypoglycemic drug of discovered in recent years, SGLT2 is mainly distributed in kidney, its effect heavily absorbs the glucose entered through glomerular filtration in uriniferous tubules, maintains the balance of the concentration of glucose in blood.Suppress the activity of SGLT2 effectively can reduce the heavily absorption of glucose in kidney, increase urine sugar concentrations, reduce blood sugar.Because the mechanism of this hypoglycemic does not rely on Regular Insulin, can share with other ofhypoglycemic medicines, therefore, SGLT2 inhibitor is very promising ofhypoglycemic medicine.
Although disclosed a series of for suppressing the compound of SGLT2 as dapagliflozin at present, canagliflozin and Ipragliflozin etc., but still need to develop curative effect, medicine is better for character, the higher compound of security is used for the treatment of diabetes, through continuous effort, the invention discloses the SGLT2 inhibitor with general formula (I) novel structure that effectively can reduce plasma glucose levels, and find that the compounds exhibit with this class formation goes out hypoglycemic activity in excellent SGLT2 inhibition and good body unexpectedly, and therefrom filter out the compound that in body, hypoglycemic activity and dapagliflozin are quite even more excellent, there is wide DEVELOPMENT PROSPECT.
Summary of the invention
The compound of the general formula (I) with pharmaceutical use that the object of the present invention is to provide a class new and pharmaceutically acceptable ester thereof.It suppresses the effect of SGLT2, can be used for preparing novel diabetes medicament.
The present invention also aims to provide preparation to have the method for the compound of general formula (I).
Another object of the present invention is the pharmaceutical preparation providing a kind of compound containing general formula (I) as effective constituent.
Detailed description content is as follows:
The present invention has synthesized a series of general formula (I) compound:
Wherein,
R 1, R 2be selected from respectively: H, F, Cl, C 1~ C 5alkyl, C 1~ C 5alkoxyl group ,-O-aryl ,-OC 1-5-aryl, cycloalkyl;
Or R 1and R 2form cycloalkyl or there is 1-4 together with the carbon atom that they connect and be selected from N, O, S, SO and/or SO 2the replacement of heteroatomic 5-12 unit or unsubstituted aromatic heterocycle;
Wherein, described cycloalkyl, aryl, aromatic heterocycle can be replaced by one or more substituting group further, and described substituting group comprises halogen atom, hydroxyl, alkyl, the alkoxyl group that replaced by halogen atom, substituted or unsubstituted aryl or aralkyl.
Preferred following general formula (I) compound:
Wherein R 1preferably certainly: C 1~ C 5alkyl, C 1~ C 5alkoxyl group;
R 2preferably certainly: F, Cl, C 1~ C 5alkyl;
Or R 1and R 2formed together with the carbon atom that they connect and there is 1-4 be selected from N, O, S, SO and/or SO 2the replacement of heteroatomic 5-12 unit or unsubstituted aromatic heterocycle;
Wherein, described aromatic heterocycle can be replaced by one or more substituting group further, the alkoxyl group that described substituting group comprises halogen atom, hydroxyl, alkyl, alkoxyl group or replaced by halogen atom, substituted or unsubstituted aryl or aralkyl.
Be preferably:
Wherein R 1be selected from: methoxyl group, oxyethyl group, propoxy-;
R 2be selected from: F, Cl, methyl, ethyl;
Or R 1and R 2the replacement of 5 yuan with 1 Sauerstoffatom or unsubstituted aromatic heterocycle is formed together with the carbon atom that they connect;
Preferred the present invention there is the compound of general formula (I) and pharmaceutically acceptable ester as shown in the table:
General formula of the present invention (I) compound is synthesized by following steps:
As shown in flow process one, at-78 DEG C, formula II compound n-Butyl Lithium processes in tetrahydrofuran (THF)/toluene Mixed Solvent, then adds lactone II I, and add methylsulfonic acid and methanol solution after question response is complete, stirred overnight at room temperature obtains formula IV compound; Lactone II I prepares reference literature R.Benhaddous, S.Czemecki etc., Carbohydr.Res., 1994,260,243-250.
At-20 DEG C, the reduction-type IV compound in acetonitrile/methylene dichloride mixed solvent with triethyl silicane and boron trifluoride diethyl etherate, can V compound for the preparation, under room temperature, full acetylated under DMAP catalysis with pyridine, aceticanhydride, and split preparation formula VI compound through recrystallization, then in tetrahydrofuran (THF), methanol-water mixed solvent, be hydrolyzed to obtain formula I through LiOH; Wherein R 1preferably certainly: methoxyl group, oxyethyl group, propoxy-; R 2preferably certainly: F, Cl, methyl, ethyl; Or R 1and R 2the replacement of 5 yuan with 1 Sauerstoffatom or unsubstituted aromatic heterocycle is formed together with the carbon atom that they connect.
The preparation method of Compounds of formula II is:
As shown in flow process two, phenol is dissolved in DMF, add salt of wormwood room temperature reaction and obtain compound 2, under ice bath, chloro-5-bromo-benzoic acid Fu Ke acidylate obtains compound 3 with 2-, obtains compound 4, be dissolved in trifluoracetic acid through triethyl silicane and boron trifluoride diethyl etherate in room temperature reduction, add urotropine to reflux to obtain compound 5 in batches, and obtain compound 6 through salt of wormwood cyclization, be dissolved in tetrahydrofuran (THF) and obtain compound 7 with sodium borohydride, Reduction of methanol, through WILLIAMS-DARLING Ton ether synthetic compound II-a; Wherein, R is selected from: C 1~ C 5alkyl, C 1~ C 5alkoxyl group ,-O-aryl ,-OC 1-5-aryl, substituted or unsubstituted cycloalkyl; II-a is the compound with general formula I I.
As shown in flow process three, the chloro-5-bromo-benzoic acid of 2-and compound 8 Fu Ke acylation reaction under aluminum chloride effect obtain compound 9, reduce to obtain Compound II per-b under triethyl silicane and boron trifluoride diethyl etherate effect; Wherein R 1preferably certainly: methoxyl group, oxyethyl group, propoxy-; R 2preferably certainly: F, Cl, methyl, ethyl; Or R 1and R 2the replacement of 5 yuan with 1 Sauerstoffatom or unsubstituted aromatic heterocycle is formed together with the carbon atom that they connect; II-b is the compound with general formula I I.
The pharmaceutically acceptable ester of general formula of the present invention (I) compound comprises the pharmaceutically acceptable ester of the form such as 6-O position hydroxyl and ethanoyl, formyl radical, methoxycarbonyl and ethoxycarbonyl of glucose fragment in molecule; Prepared by method shown in available following formula:
The R of Compound I monovalent 3cOCl process, esterification on the 6-O position of the glucose fragment of Compound I, obtained corresponding ester; Wherein, R 3be selected from the pharmaceutically acceptable group such as Me, Et, MeO and EtO, preferred MeO and EtO.
The present invention also comprises pharmaceutical preparation, and said preparation comprises as general formula (I) compound of promoting agent or its ester or pharmaceutically acceptable carrier.Above-mentioned pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, refer to one or more inertia, atoxic solid or liquid filler material, thinner, auxiliary agents etc., they are not reverse has an effect with active compound or patient.
The formulation of the present composition can be formulation conventional in the pharmaceuticies such as tablet, capsule, pill, soft capsule.
Tablet for oral use and capsule contain traditional vehicle as weighting material, thinner, lubricant, dispersion agent and tackiness agent.
The various formulations of pharmaceutical composition of the present invention can be prepared according to the method known in pharmaceutical field.
The dosage of above promoting agent will be different because of formula.
Usually, proved favourable amount, for reaching results needed, the total amount of formula (I) compound of every kilogram of administration in every 24 hours is about 0.01-200mg, and preferred total amount is 0.1-100mg/kg; If necessary, with the form administration of single dose several times.
But if necessary, also can depart from above-mentioned consumption, namely this depends on the type of experimenter to be treated and body weight, the individual type to the behavior of medicine, the character of disease and seriousness, preparation and administration and administration time and interval.
In the present invention compound body in hypoglycemic activity can measure by using Analytical system as described below.
Normal mouse oral glucose tolerance test (OGTT)
10 week age Kunming kind cleaning grade mouse, body weight 18 ~ 22g, male, be divided into 11 groups at random, blank group (blank solvent), positive drug control group 1 (Dapagliflozin:1.5mg/kg (3.7 μm of ol/kg)), positive drug control group 2 (N1,N1-Dimethylbiguanide: 100mg/kg), test-compound group (3.7 μm of ol/kg), often organizes 8.
Before experiment, mouse fasting can't help water 12 hours, the equal oral administration gavage administration of each group, and blood is got in docking, measures blood glucose value (being designated as-30min).Then 11 groups of mouse respectively gavage give blank solvent, Dapagliflozin, N1,N1-Dimethylbiguanide 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 measures blood glucose value (mmol/L).Result is as following table.
Table 1: after normal mouse single-dose 2h blood glucose value change ( n=8).
Note: * P≤0.05, * * P≤0.01 is Student ' the s t assay relative to blank group.
The tolerance test of normal mouse oral glucose shows, all test-compounds all have certain hypoglycemic effect, and wherein Compound I-1 and I-5 obviously can improve the sugar tolerance of normal mouse, and in body, hypoglycemic activity is suitable with Dapagliflozin, even better, show excellent hypoglycemic activity.
In the present invention, the body of compound is interior promotes that the activity of glucose in urine can measure by using Analytical system as described below.
10 week age Kunming kind cleaning grade mouse, body weight 18 ~ 22g, male, be divided into 11 groups at random, blank group (blank solvent), positive drug control group 1 (Dapagliflozin:1.5mg/kg (3.7 μm of ol/kg)), positive drug control group 2 (N1,N1-Dimethylbiguanide: 100mg/kg), test-compound group (3.7 μm of ol/kg), often organizes 8.
Before experiment, mouse fasting can't help water 12 hours, and the equal oral administration gavage administration of each group, measures glucose in urine (being designated as-30min).Then 11 groups of mouse respectively gavage give blank solvent, Dapagliflozin, N1,N1-Dimethylbiguanide and test-compound, measure urine sugar 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 measures urine sugar value.
The mensuration of urine sugar value immerses in urine by Tes-Tape band, and drenched (about 1-2 kind second) takes out afterwards; Test paper is taken out to remove unnecessary urine along container edge; Within 30-60 second, observe test paper band color and contrast with color board, recording result.Result judges: (test paper represents detected result by light blue to red-brown change) light bluely indicates without glucose in urine, represents with "-"; Red-brown indicates glucose in urine, and darker "+" number the more, in urine, glucose concn is higher.Result is as following table.
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 I-1, I-5 and I-8 can obviously promote that glucose in urine is discharged, and shows that it has good SGLT2 inhibit activities.
Embodiment
Below in conjunction with embodiment, the invention will be further described.It should be noted that, following embodiment only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
Embodiment 1
(the bromo-2-chloro-phenyl-of 5-) (4-oxyethyl group-3-fluorophenyl) ketone (IIa-1)
Be equipped with in the mono-neck bottle of 100ml of calcium chloride tube, the chloro-5-bromo-benzoic acid (5.0g, 21.23mmol) of 2-is suspended in 20ml methylene dichloride, drips oxalyl chloride (5.49ml under stirring, 63.69mmol), drip and finish, with a DMF catalysis, room temperature reaction 3h, remove solvent and unnecessary oxalyl chloride under reduced pressure, resistates 25ml methylene dichloride dissolves, and puts cryosel bath and is cooled to about-10 DEG C, add AlCl in batches 3(3.40g, 24.98mmol), finishing stirs to reaction solution from yellow-green colour becomes yellow thick liquid, start to drip 2-fluorobenzene ether (2.84g, 20.84mmol), in controlling, temperature is lower than 0 DEG C, drip and finish, react about 45min in 0 DEG C and react complete, in the 1N hydrochloric acid (100ml) that impouring is cold, being stirred to reddish-brown reaction solution becomes closely colourless, methylene dichloride (25ml × 3) extracts, organic phase is washed with 1N NaOH (30ml × 1), saturated aqueous common salt (50ml × 2) washs, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, residual solid obtains the colourless column crystallization of 5.3g with ethyl alcohol recrystallization, fusing point: 136-138 DEG C, yield: 72.0%.
1H NMR(300MHz，DMSO-d 6)δ：7.80-7.76(m，2H，Ar-H)，7.63-7.55(m，2H，Ar-H)，7.46-7.43(m，1H，Ar-H)，7.32-7.27(m，1H，Ar-H)，4.22(q，J＝6.96Hz，2H，CH 3 CH 2 -O)，1.38(t，J＝6.95Hz，3H， CH 3 CH 2-O)。
(the bromo-2-chloro-phenyl-of 5-) (4-oxyethyl group-3-chloro-phenyl-) ketone (IIa-2)
The same IIa-1 of synthetic method, with 2-chlorophenetole for raw material, obtained colourless crystallization IIa-2 (4.7g), fusing point: 126-128 DEG C, yield: 82.2%.
1H NMR(300MHz，DMSO-d 6)δ：7.80-7.76(m，3H，Ar-H)，7.63-7.55(m，2H，Ar-H)，7.30(d，J＝8.58Hz，1H，Ar-H)，4.25(q，J＝6.97Hz，2H，CH 3 CH 2 O)，1.39(t，J＝6.95Hz，3H， CH 3 CH 2-O)。
(the bromo-2-chloro-phenyl-of 5-) (4-oxyethyl group-3-aminomethyl phenyl) ketone (IIa-3)
The same IIa-1 of synthetic method, with 2-tolyl ethyl ether for raw material, obtained colourless crystallization IIa-3 (5.6g), fusing point: 93-95 DEG C, yield: 76.1%.
1H NMR(300MHz，DMSO-d 6)δ：7.77-7.70(m，2H，Ar-H)，7.60-7.47(m，3H，Ar-H)，7.05(d，J＝8.64Hz，1H，Ar-H)，4.15(q，J＝6.94Hz，2H，CH 3 CH 2 -O)，2.18(s，3H，Ar- CH 3 )，1.39(t，J＝6.95Hz，3H， CH 3 CH 2-O)。
(the bromo-2-chloro-phenyl-of 5-) (2-diphenylene-oxide) ketone (IIa-4)
The same IIa-1 of synthetic method take dibenzofuran as raw material, obtained colourless column crystallization IIa-4 (4.9g), fusing point: 169-171 DEG C, yield: 83.5%.
1H NMR(300MHz，DMSO-d 6)δ：8.63(d，J＝1.32Hz，1H，Ar-H)，8.32(d，J＝7.41Hz，1H，Ar-H)，7.93-7.75(m，5H，Ar-H)，7.60(d，J＝8.46Hz，2H，Ar-H)，7.47-7.42(m，1H，Ar-H)。
Wherein, IIa-1 ~ IIa-4 is the compound with general formula 9.
Embodiment 2
The chloro-2-of the bromo-1-of 4-(4-oxyethyl group-3-luorobenzyl) benzene (II-1)
Be equipped with in the mono-neck bottle of 100ml of Calcium Chloride Powder Anhydrous drying tube, raw material II a-1 (5.3g, 15.0mmol) is dissolved in the mixed solvent of 20ml methylene dichloride and 20ml acetonitrile, puts cryosel bath and is cooled to about-5 DEG C, drip Et under stirring 3siH (5.3ml, 33.0mmol), drips BF after stirring again 3et 2o (3.8ml, 30.0mmol), finish, naturally room temperature is risen in ice bath, stirring is spent the night, in ice-water bath cooling downhill reaction liquid, drip 2N NaOH be adjusted to solution PH and be about 8-9, thin up, methylene dichloride (25ml × 3) extracts, and organic phase is washed with 1N hydrochloric acid (30ml × 2), saturated aqueous common salt (40ml × 1) washs, anhydrous sodium sulfate drying, filters, removes solvent under reduced pressure, resistates obtains 5.1g colourless oil liquid through column chromatography purification, yield: 97.3%.
1H NMR(300MHz，DMSO-d 6)δ：7.56(d，J＝2.16Hz，1H，Ar-H)，7.48-7.38(m，2H，Ar-H)，7.10-7.04(m，2H，Ar-H)，6.95(d，J＝8.37Hz，1H，ArH)，4.05(q，J＝6.97Hz，2H，CH 3 CH 2 -O)，3.99(s，2H，Ar- CH 2 -Ar)，1.33(t，J＝6.97Hz，3H， CH 3 CH 2-O)。
The chloro-2-of the bromo-1-of 4-(4-oxyethyl group-3-chlorobenzyl) benzene (II-2)
The same II-1 of synthetic method is that raw material obtains colorless oil, yield with IIa-2: 93.7%.
1H NMR(300MHz，DMSO-d 6)δ：7.58(d，J＝2.19Hz，1H，Ar-H)，7.48-7.44(m，2H，Ar-H)，7.28(d，J＝1.80Hz，1H，Ar-H)，7.13-7.04(m，2H，Ar-H)，4.06(q，J＝6.96Hz，2H，CH 3 CH 2 -O)，3.99(s，2H，Ar- CH 2 -Ar)，1.33(t，J＝6.96Hz，3H， CH 3 CH 2-O)。
The chloro-2-of the bromo-1-of 4-(3-methyl-4-ethoxy benzyl) benzene (II-3)
The same II-1 of synthetic method is that raw material obtains colorless oil, yield with IIa-3: 95.6%.
1H NMR(300MHz，DMSO-d 6)δ：7.48-7.37(m，3H，Ar-H)，6.98-6.81(m，3H，Ar-H)，3.96(q，J＝6.95Hz，2H，CH 3 CH 2 -O)，3.93(s，3H，Ar- CH 3 )，2.10(s，2H，Ar- CH 2 -Ar)，1.31(t，J＝6.95Hz，3H， CH 3 CH 2-O)。
2-(the bromo-2-chlorobenzyl of 5-) diphenylene-oxide (II-4)
The same II-1 of synthetic method is that raw material obtains colourless column crystallization, fusing point: 102-104 DEG C, yield: 83.2% with IIa-4.
1H NMR(300MHz，DMSO-d 6)δ：8.12(d，J＝7.32Hz，1H，Ar-H)，8.01(s，1H，Ar-H)，7.70-7.59(m，3H，Ar-H)，7.54-7.36(m，5H，Ar-H)，4.23(s，2H，Ar- CH 2 -Ar)。
Wherein, II-1 ~ II-4 is the compound with general formula I I-b.
Embodiment 3
2-(4-(the chloro-5-benzoyl bromide of 2-) phenoxy group) ethyl acetate (3)
In 100ml round-bottomed flask, phenol (5.0g, 53.1mmol), ethyl chloroacetate (6.7mL, 63.8mmol) is dissolved in 40mLDMF, disposablely in stirring adds salt of wormwood (22.0g, 159.4mmol), stirring at room temperature 3h.In reaction solution, add saturated nacl aqueous solution dissolve to salt of wormwood, ethyl acetate (40ml × 3) extracts, organic phase is respectively to wash (30ml × 2), 1N sodium hydroxide (20ml × 2) washs, saturated aqueous common salt (25ml × 2) washs, anhydrous sodium sulfate drying, filters, and filtrate decompression is steamed and desolventized to obtain 0.86g light yellow liquid.
Be equipped with in the mono-neck bottle of 100ml of Calcium Chloride Powder Anhydrous drying tube, the chloro-5-bromo-benzoic acid of 2-(5g, 21.2mmol) be suspended in 40mL dry methylene chloride, add a DMF catalysis, oxalyl chloride (the 7.3mL that slow dropping 10mL dry methylene chloride is dissolved, 131.4mmol), complete stirring at room temperature 3h is dripped.Stopping stirring, removes solvent under reduced pressure and unnecessary oxalyl chloride obtains yellow oil.Yellow oil is dissolved in 40mL dry methylene chloride, puts ice bath and be cooled to 0 DEG C, add AlCl in batches 3(8.5g, 63.7mmol) keep interior temperature lower than 5 DEG C, finish, stir and slowly drip the 2-ethyl phenoxyacetate (3.8g of dry methylene chloride dissolving again, 21.2mmol), drip and finish 0 DEG C of stirring 5h, stop stirring, reaction solution is poured in frozen water (100ml), stir 15min, dichloromethane extraction (40ml × 3), organic phase is washed with 1N hydrochloric acid (20ml × 2), saturated aqueous common salt (25ml × 2) washs, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained solid is through ethyl alcohol recrystallization, obtain 4.7g white crystals, fusing point: 78-79 DEG C, yield: 55.6%.
1H NMR(300MHz，DMSO-d 6)δ：7.78(t，J＝4.92Hz，2H，Ar-H)，7.68(d，J＝8.7Hz，2H，Ar-H)，7.55(d，J＝8.37Hz，1H，Ar-H)，7.08(d，J＝8.73Hz，2H，Ar-H)，4.92(s，2H，O- CH 2 -CO)，4.17(q，J＝7.08Hz，2H，-COO CH 2 -)，1.21(t，3H，J＝7.08Hz，-CH 2 CH 3 )。
Embodiment 4
2-(4-(the chloro-5-bromobenzyl of 2-) phenoxy group) ethyl acetate (4)
Compound 3 (4g, 10.0mmol) is dissolved in 20mL dry methylene chloride and the dry acetonitrile of 20mL, adds Et 3siH (6.0mL, 37.4mmol), puts frozen water and is cooled to 0 DEG C, slowly drips the BF that 5ml dry methylene chloride is dissolved 3et 2o (5.0mL, 39.5mmol), adds rear stirring at room temperature 12h.20mL 1N potassium hydroxide solution is added in reaction solution, stir 15min, ethyl acetate (30ml × 3) extracts, 1N sodium hydroxide (15ml × 2) washs, and saturated aqueous common salt (20ml × 2) washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, obtains 2.8g colourless oil liquid through column chromatography purification, yield 72.5%.
1HNMR(300MHz，CDCl 3)δ：7.30(m，3H)，7.11(d，J＝8.62Hz，2H)，6.97(d，J＝8.63Hz，2H)，4.60(s，2H)，4.30(q，J＝7.12Hz，2H)，3.99(s，2H)，1.29(t，J＝7.13Hz，3H)。
Embodiment 5
2-(4-(the chloro-5-bromobenzyl of 2-)-2-formvlphenoxv) ethyl acetate (5)
Under ice bath cooling, urotropine (1g, 6.26mmol) mix with 10ml trifluoracetic acid, compound 4 (2g is added in said mixture, 5.20mmol) reaction solution is light red, put oil bath reflux and be about 1h, stop stirring, to be cooled to after room temperature in impouring frozen water, stir, sodium carbonate carefully alkalize to PH be 8-9, extract through ethyl acetate (20ml × 3), organic phase is washed with saturated aqueous common salt (20ml × 2), anhydrous sodium sulfate drying, filter, filtrate decompression is steamed and is desolventized to obtain yellow oil, column chromatography purification obtains 0.6g white plates crystal, fusing point: 68-70 DEG C, yield: 23.4%.
1H NMR(300MHz，DMSO-d 6)δ：10.39(s，1H，C HO)，7.64(d，J＝2.25Hz，1H，Ar-H)，7.51(d，J＝7.98Hz，1H，Ar-H)，7.48(t，J＝3.12Hz，2H，Ar-H)，7.41(d，J＝8.52Hz，1H，Ar-H)，7.13(d，J＝8.43Hz，1H，Ar-H)，4.96(s，2H，O- CH 2 -CO)，4.19(q，J＝7.10Hz，2H，-COO CH 2 -)，4.05(s，2H，Ar- CH 2 -Ar)，1.21(t，J＝7.10Hz，3H，-CH 2 CH 3 )。
Embodiment 6
5-(the bromo-2-chlorobenzyl of 5-) coumarilic acid ethyl ester (6)
Compound 5 (2.0g, 4.9mmol) be dissolved in 10ml DMF, add Anhydrous potassium carbonate (0.9g, 6.3mmol), heat 92-94 DEG C and stir 4h, react, in the saturated aqueous common salt (30ml) that impouring is ice-cold, ethyl acetate (20ml × 3) extracts, and organic phase is washed with 1N hydrochloric acid (20ml × 1) successively, saturated aqueous common salt (25ml × 2) washs, anhydrous sodium sulfate drying, filters, removes solvent under reduced pressure and obtain 1.6g white solid, fusing point: 115-117 DEG C, yield: 80.8%.
1H NMR(300MHz，DMSO-d 6)δ：7.72(s，1H，Ar-H)，7.67(d，J＝8.61Hz，1H，Ar-H)，7.62(d，J＝2.22Hz，1H，Ar-H)，7.58(s，1H，Ar-H)，7.47(d，J＝2.31Hz，1H，Ar-H)，7.42(m，2H，Ar-H)，4.36(q，J＝7.10Hz，2H，-COO CH 2 -)，4.18(s，2H，Ar- CH 2 -Ar)，1.32(t，J＝7.10Hz，3H，-CH 2 CH 3 )。
Embodiment 7
5-(the bromo-2-chlorobenzyl of 5-) cumarone-2-methyl alcohol (7)
In the mono-neck bottle of 50ml of configuration Calcium Chloride Powder Anhydrous drying tube, compound 6 (0.54g, 1.37mmol) be dissolved in 5ml THF, be placed in ice-water bath and be cooled to about 0 DEG C, add NaBH4 (0.11g in batches, 2.74mmol), finish, stir post-heating to backflow, dropwise drip methyl alcohol 0.5ml, reaction is violent produces a large amount of bubble, drip complete back flow reaction 0.5h, react, in impouring frozen water, stir, ethyl acetate (20ml × 3) extracts, organic phase is washed with saturated aqueous common salt (25ml × 2), anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure and obtain 0.47g white solid, fusing point: 98-100 DEG C, yield 97.5%.
1H NMR(300MHz，DMSO-d 6)δ：7.54(d，J＝2.13Hz，1H，Ar-H)，7.47(d，1H，Ar-H)，7.44(d，J＝2.31Hz，1H，Ar-H)，7.42(s，1H，Ar-H)，7.40(m，J＝1.96Hz，1H，Ar-H)，7.13(m，1H，Ar-H)，6.70(s，1H，Ar-H)，5.48(t，J＝5.82Hz，1H，OH)，4.54(d，J＝5.61Hz，2H，Ar- CH 2 -O)，4.13(s，2H，Ar- CH 2 -Ar)。
Embodiment 8
5-(the bromo-2-chlorobenzyl of 5-)-2-ethoxymethyl cumarone (II-5)
Under ice bath cooling, NaH (0.15g, 3.13mmol) be added to compound 7 (0.5g, in THF (5ml) solution 1.4mmol), remove ice bath, stirring at room temperature to reaction solution bubble-free emerges (about 1h), add catalytic amount TBAB, drip monobromethane (0.17g, 1.57mmol), drip complete temperature rising reflux 1h, react, in impouring frozen water, ethyl acetate (25ml × 3) extracts, and saturated aqueous common salt (25ml × 2) washs, anhydrous sodium sulfate drying, filter, pressure reducing and steaming solvent obtains 0.53g yellow oil II-5, yield 80.1%.
1H NMR(300MHz，DMSO-d 6)δ：7.51(d，J＝2.07Hz，1H，Ar-H)，7.47(d，1H，Ar-H)，7.44(d，J＝2.07Hz，1H，Ar-H)，7.42(s，1H，Ar-H)，7.40(m，1H，Ar-H)，7.13(m，1H，Ar-H)，6.78(s，1H，Ar-H)，4.51(s，2H，Ar- CH 2 -O)，4.10(s，2H，Ar- CH 2 -Ar)，3.48(q，J＝6.99Hz，2H，O CH 2 CH 3)，1.10(t，J＝7.00Hz，3H，OCH 2 CH 3 )。
5-(the bromo-2-chlorobenzyl of 5-)-2-benzyloxymethyl cumarone (II-6)
The same II-5 of synthetic method, raw materials used is bromobenzyl, obtains white solid 2g, fusing point: 74-76 DEG C, productive rate: 96.3%.
1H NMR(300MHz，CDCl 3)δ：7.43(d，J＝8.43Hz，1H，Ar-H)，7.31(s，1H，Ar-H)，7.27-7.20(m，8H，Ar-H)，7.11-7.08(m，1H，Ar-H)，6.64(s，1H，Ar-H)，4.63(s，2H，Ar- CH 2 -O)，4.62(s，2H，Ph- CH 2 -O)，4.13(s，2H，Ar- CH 2 -Ar)。
5-(the bromo-2-chlorobenzyl of 5-)-2-(2-tetrahydrofuran (THF) methoxyl methyl) cumarone (II-7)
The same II-5 of synthetic method, colourless oil liquid 1.5g, productive rate: 80.2%.
1H NMR(300MHz，CDCl 3)δ：7.41(d，J＝8.43Hz，1H，Ar-H)，7.33(s，1H，Ar-H)，7.30-7.22(m，3H，Ar-H)，7.11-7.08(m，1H，Ar-H)，6.63(s，1H，Ar-H)，4.67(s，2H，Ar- CH 2 -O)，4.12(s，2H，Ar- CH 2 -Ar)，4.10-4.06(m，1H，O CHCH 2CH 2)，3.92-3.75(m，2H，O CH 2 CHO)，3.58-3.50(m，2H，O CH 2 CH 2)，1.96-1.58(m，4H，CH CH 2 CH 2 CH 2)。
Wherein, II-5 ~ II-7 is the compound with general formula I I-a.
Embodiment 9
The chloro-3-of 4-(4-oxyethyl group-3-luorobenzyl) benzene-1-base-α/β-D-methoxyl group glucopyranoside (IV-1)
Be equipped with in the 100ml three-necked bottle of-100 DEG C of thermometers and plug, Compound II per-1 (0.54g, 1.42mmol) be dissolved in 5mL dry tetrahydrofuran and 5mL dry toluene, nitrogen protection, be cooled to-78 DEG C, slow dropping n-Butyl Lithium (1.04mL, 1.56mmol, 1.6M),-78 DEG C of reaction 0.5h after adding, slowly drip the gluconolactone (1g of the trimethylchlorosilane protection that 5mL dry toluene dissolves again, 2.13mmol), at-78 DEG C, 3h is reacted after adding, add the methanesulfonic 0.3mL of 2mL dissolve with methanol again, room temperature reaction 16h is risen to after adding, after reaction terminates, drip saturated sodium bicarbonate in reaction solution to emerge to bubble-free, ethyl acetate (50mL × 3) extracts, merge organic phase, wash with saturated sodium bicarbonate solution (25mL × 2) successively, saturated aqueous common salt (25mL × 2) washs, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure and obtain yellow oil, column chromatographic isolation and purification (methylene dichloride: methyl alcohol=30: 1) obtain white solid 0.3g (mixtures of two kinds of configurations), fusing point: 60-62 DEG C, yield: 42.9%.
1H NMR(300MHz，DMSO-d 6)δ：7.52-7.40(m，3H，Ar-H)，7.05-6.88(m，3H，Ar-H)，4.99(d，J＝5.46Hz，2H，-O CH 2 -)，4.54(t，J＝5.68Hz，1H，-O CH-)，4.07-3.99(m，5H，Ar- CH 2 -Ar，-O CH-，-O CH 2 CH 3)，3.73-3.68(m，1H，-O CH-)，3.49-3.42(m，1H，-O CH)，3.31-3.08(m，4H，- OH)，2.92(s，3H，-O CH 3 )，1.31(t，J＝6.96Hz，3H，-OCH 2 CH 3 )。
Embodiment 10
The chloro-3-of 4-(4-oxyethyl group-3-luorobenzyl) benzene-1-base-β-D-2,3,4,6 ,-four-O-ethanoyl glucopyranosides (VI-1)
Compound IV-1 (0.3g, 0.61mmol) is dissolved in 5mL methylene dichloride and 5mL acetonitrile, adds Et3SiH (0.27mL, 1.71mmol), is cooled to-15 DEG C, slowly drips the BF of dchloromethane 3et 2o (0.11mL, 0.85mmol), drips to finish to react at-10 DEG C and spends the night.Reaction terminates to add saturated sodium bicarbonate in backward reaction solution emerges to bubble-free, and extraction into ethyl acetate, merges organic phase, and saturated aqueous common salt (20mL × 2) washs, and anhydrous sodium sulfate drying, suction filtration, obtains 0.2g faint yellow solid.Above-mentioned crude product (0.2g, 0.43mmol) is dissolved in 5ml methylene dichloride, adds pyridine (0.42mL, 4.32mmol) successively under ice bath, the DMAP of diacetyl oxide (0.5mL, 4.32mmol) and catalytic amount, adds rear room temperature reaction 2h.Reaction terminates to add 20ml water in backward reaction solution, and methylene dichloride (30mL × 3) extracts, and merges organic phase, uses 1N hydrochloric acid (20mL × 2) respectively, and saturated aqueous common salt (20mL × 2) washs, anhydrous Na 2sO 4drying, suction filtration, removes solvent under reduced pressure, and gained solid obtains white powdery solids 0.18g through ethyl alcohol recrystallization, fusing point: 132-134 DEG C, productive rate: 48.9%.
1H NMR(300MHz，DMSO-d 6)δ：7.44-7.25(m，3H，Ar-H)，7.08-6.89(m，3H，Ar-H)，5.35(t，J＝9.48Hz，1H，-O CH-)，5.07(t，J＝9.45Hz，1H，-O CH-)，4.96(t，J＝9.64Hz，1H，-O CH-)，4.66(d，J＝9.69Hz，1H，-O- CH-Ar)，4.10-3.98(m，7H，Ar- CH 2 -Ar，-O CH-，-O CH 2 -，-O CH 2 CH 3)，2.01(s，3H， CH 3 CO)，1.99(s，3H， CH 3 CO)，1.92(s，3H， CH 3 CO)，1.70(s，3H， CH 3 CO)，1.31(t，J＝6.96Hz，3H，-OCH 2 CH 3 )。
Embodiment 11
The chloro-3-of 4-(4-oxyethyl group-3-luorobenzyl) benzene-1-base-β-D-glucopyranoside (I-1)
Compound VI-1 (0.18g, 0.30mmol) be dissolved in 4mL tetrahydrofuran (THF), in 6mL methyl alcohol and 2mL water, add hydronium(ion) Lithium Oxide 98min (0.07g, 1.7mmol), room temperature reaction spends the night, question response terminates rear concentrating under reduced pressure, residual liquid is with 30ml acetic acid ethyl dissolution, use the potassium hydrogen sulfate solution (10mL × 2) of 5% respectively, saturated aqueous common salt (15mL × 2) washs, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, obtain colorless oil, column chromatographic isolation and purification (methylene dichloride: methyl alcohol=30: 1) obtain white solid 0.1g, fusing point: 66-68 DEG C, productive rate: 76.9%.
1H NMR(300MHz，DMSO-d 6)δ：7.39-7.35(m，2H，Ar-H)，7.27-7.23(m，1H，Ar-H)，7.07-6.98(m，2H，Ar-H)，6.94-6.91(m，1H，Ar-H)，4.96(d，J＝5.53Hz，2H，-O CH 2 -)，4.84(d，J＝5.67Hz，1H，-O CHAr)，4.50(t，J＝5.68Hz，1H，-O CH-)，4.08-3.99(m，5H，Ar- CH 2 -Ar，-O CH-，-O CH 2 CH 3)，3.73-3.68(m，1H，-O CH-)，3.49-3.42 (m，1H，-O CH)，3.31-3.08(m，4H，- OH)，1.31(t，J＝6.96Hz，3H，-OCH 2 CH 3 )；
13C NMR(75MHz，DMSO-d 6)δ：153.0，149.8，139.7，137.1，131.8，130.8，128.6，127.5，124.5，116.1，115.8，114.8，81.1，80.6，78.2，74.6，70.2，64.2，61.3，59.7，37.4，14.5；
MS(ESI，m/z)：449.8[M+Na] +。
Embodiment 12
The chloro-3-of 4-(4-oxyethyl group-3-chlorobenzyl) benzene-1-base-β-D-glucopyranoside (I-2)
The same I-1 of synthetic method, obtains white solid 0.30g, fusing point: 78-79 DEG C, productive rate: 91.3%.
1H NMR(300MHz，DMSO-d 6)δ：7.36(d，J＝8.19Hz，1H，Ar-H)，7.31-7.30(m，1H，Ar-H)，7.25-7.21(m，1H，Ar-H)，6.97-6.92(m，2H，Ar-H)，6.80(d，J＝8.28Hz，1H，Ar-H)，4.96(d，J＝5.48Hz，2H，-O CH 2 -)，4.83(d，J＝5.55Hz，1H，-O- CH-Ar)，4.50(t，J＝5.68Hz，1H，-O CH-)，4.06-3.92(m，5H，Ar CH 2 Ar，-O CH-，-O CH 2 CH 3)，3.73-3.68(m，1H，-O CH-)，3.49-3.43(m，1H，-O CH)，3.30-3.07(m，4H，- OH)，1.30(t，J＝6.93Hz，3H，-OCH 2 CH 3 )；
13C NMR(75MHz，DMSO-d 6)δ：152.1，139.7，137.1，132.6，131.8，130.8，129.7，128.7，128.2，127.5，121.0，113.7，81.1，80.6，78.2，74.6，70.2，64.2，61.3，37.2，14.5；
MS(ESI，m/z)：466.3[M+Na] +。
Embodiment 13
The chloro-3-of 4-(4-oxyethyl group-3-methyl-benzyl) benzene-1-base-β-D-glucopyranoside (I-3)
The same I-1 of synthetic method, white solid 0.31g, fusing point 75-76 DEG C, productive rate: 90.2%.
1H NMR(300MHz，DMSO-d 6)δ：7.39-7.36(m，2H，Ar-H)，7.27-7.22(m，2H，Ar-H)，7.11-7.01(m，2H，Ar-H)，4.96(d，J＝5.66Hz，2H，-O CH 2 -)，4.84(d，J＝5.55Hz，1H，-O- CH-Ar)，4.44(t，J＝5.60Hz，1H，-O CH-)，4.06-3.99(m，5H，Ar- CH 2 -Ar，-O CH-，-O CH 2 CH 3)，3.73-3.68(m，1H，-O CH-)，3.47-3.44(m，1H，-O CH)，3.23-3.11(m，4H，- OH)，2.09(s，3H，Ar CH 3 )，1.32(t，J＝6.94Hz，3H，-OCH 2 CH 3 )；
13C NMR(75MHz，DMSO-d 6)δ：154.9，139.5，137.8，131.8，130.8，130.7，130.6，128.6，127.1，126.8，125.4，111.1，81.1，80.6，78.2，74.6，70.2，63.0，61.3，37.6，16.0，14.7；
MS(ESI，m/z)：445.9[M+Na] +。
Embodiment 14
The chloro-3-of 4-(diphenylene-oxide-2-methyl) benzene-1-base-β-D-glucopyranoside (I-4)
The same I-1 of synthetic method, obtains white solid 0.45g, fusing point 88-90 DEG C, productive rate: 95.7%.
1H NMR(300MHz，DMSO-d 6)δ：8.10(d，J＝7.53Hz，1H，Ar-H)，7.96(s，1H，Ar-H)，7.69-7.60(m，3H，Ar-H)，7.53-7.25(m，5H，Ar-H)，4.94(d，J＝5.72Hz，2H，-O CH 2 )，4.85(d，J＝5.67Hz，1H，-O CHAr)，4.43(t，J＝5.76Hz，1H，-O CH)，4.23(s，2H，Ar CH 2 Ar)，4.02-3.99(m，1H，-O CH-)，3.71-3.66(m，1H，-O CH)，3.47-3.42(m，1H，-O CH)，3.26-3.08(m，4H，- OH)；
13C NMR(75MHz，DMSO-d 6)δ：155.7，154.0，139.7，137.5，134.3，131.9，130.9，128.7，128.1，127.5，127.4，123.5，123.4，122.9，121.0，120.8，111.5，111.4，81.1，80.6，78.2，74.7，70.2，61.3，38.3；
MS(ESI，m/z)：477.8[M+Na] +。
Embodiment 15
The chloro-3-of 4-(2-ethoxymethyl cumarone-5-methyl) benzene-1-base-β-D-glucopyranoside (I-5)
The same I-1 of synthetic method, obtains white solid 0.11g, fusing point: 64-65 DEG C, productive rate: 80.9%.
1H NMR(300MHz，DMSO-d 6)δ：7.48(d，J＝8.49Hz，1H，Ar-H)，7.40-7.36(m，3H，Ar-H)，7.26-7.23(m，1H，Ar-H)，7.17-7.13(m，1H，Ar-H)，6.81(s，1H，Ar-H)，4.95(d，J＝5.64Hz，2H，-O CH 2 )，4.84(d，J＝5.64Hz，1H，-O- CH-Ar)，4.53(s，2H，Ar- CH-O)，4.44(t，J＝5.62Hz，1H，-O CH)，4.14(s，2H，Ar- CH 2 -Ar)，4.01-3.98(m，3H，-O CH-，-O CH 2 )，3.72-3.66(m，1H，-O CH)，3.54-3.40(m，3H，-O CH，O CH 2 CH 3)，3.26-3.10(m，4H，- OH)，1.12(t，J＝6.99Hz，3H， CH 3 )；
13C NMR(75MHz，DMSO-d 6)δ：154.9，153.1，137.7，134.1，131.9，130.9，128.6，127.8，127.3，125.2，120.7， 110.8，105.5，81.1，80.6，78.2，75.6，74.6，71.3，70.2，69.4，38.3，14.2；
MS(ESI，m/z)：485.9[M+Na] +。
Embodiment 16
The chloro-3-of 4-(2-benzyloxymethyl cumarone-5-methyl) benzene-1-base-β-D-glucopyranoside (I-6)
The same I-1 of synthetic method, obtains white solid 0.23g, fusing point 57-58 DEG C, productive rate: 87.1%.
1H NMR(300MHz，DMSO-d 6)δ：7.49(d，J＝8.43Hz，1H，Ar-H)，7.31(s，1H，Ar-H)，7.27-7.20(m，8H，Ar-H)，7.11-7.08(d，J＝8.37Hz，1H，Ar-H)，6.64(s，1H，Ar-H)，4.98(d，J＝5.52Hz，2H，-O CH 2 -)，4.87(d，J＝5.52Hz，1H，-O- CH-Ar)，4.62(s，2H，Ar- CH 2 -O)，4.55(s，2H，Ph- CH 2 -O)，4.46(t，J＝5.22Hz，HOCH 2 CH-O)，4.14(s，2H，Ar- CH 2 -Ar)，4.01(t，J＝7.32Hz，1H，-O CH-)，3.71(t，J＝6.3Hz，1H，-O CH-)，3.38(t，J＝4.5Hz，1H，-O CH)，3.26-3.16(m，4H，- OH)；
13C NMR(75MHz，DMSO-d 6)δ：154.7，153.2，139.7，137.8，137.7，134.1，131.1，130.9，128.7，128.2，127.8，127.6，127.5，127.3，125.3，120.8，110.8，105.8，81.1，80.6，78.2，74.6，71.3，70.2，63.9，61.3，59.7，38.3；
MS(ESI，m/z)：548.1[M+Na] +。
Embodiment 17
The chloro-3-of 4-(2-(2-tetrahydrofuran (THF) methoxyl methyl) cumarone-5-methyl) benzene-1-base-β-D-glucopyranoside (I-7)
The same I-1 of synthetic method, obtains white solid 0.19g, fusing point 52-54 DEG C, productive rate: 77.2%.
1H NMR(300MHz，DMSO-d 6)δ：7.47(d，J＝8.34Hz，1H，Ar-H)，7.38-7.16(m，5H，Ar-H)，6.82(d，J＝8.36Hz，1H，Ar-H)，4.58(d，J＝5.43Hz，2H，-O CH 2 )，4.48(d，J＝6.52Hz，1H，-O- CH-Ar)，4.23(s，2H，Ar- CH-O)，4.08(s，2H，Ar- CH 2 -Ar)，4.01-3.92(m，2H，CH 2 CH-O)，3.82-3.69(m，3H，O CH 2 CHO，-O CH)，3.60-3.5(m，3H，-O CH-，-O CH 2 )，3.43(t，J＝4.50Hz，1H，-O CH)，3.28-3.19(m，4H，- OH)，1.98-1.76(m，4H，CH CH 2 CH 2 CH 2)；
13C NMR(75MHz，DMSO-d 6)δ：154.9，153.1，137.7，134.1，131.9，130.9，128.6，127.8，127.3，125.2，120.7，110.8，105.5，78.2，77.1，74.6，72.3，70.2，69.4，67.2，64.7，61.3，59.7，38.3，27.6，25.1；
MS(ESI，m/z)：541.9[M+Na] +。
Embodiment 18
The chloro-3-of 4-(4-oxyethyl group-3-luorobenzyl) benzene-1-base-6-O-methoxycarbonyl-β-D-glucopyranoside (I-8)
Compound I-1 (0.5g, 1.20mmol), triethylamine (0.11g, 1.20mmol) be dissolved in 20ml methylene dichloride, put in ice-water bath and cool, drip 0.11g Vinyl chloroformate, drip and finish, mixture stirred overnight at room temperature, reaction system 30ml saturated aqueous common salt cancellation, ethyl acetate (20mL × 3) extracts, merge organic phase, saturated aqueous common salt (10mL × 2) washs, anhydrous sodium sulfate drying, suction filtration, remove solvent under reduced pressure, gained resistates obtains I-8 sterling through column chromatography purification, clear crystal 0.4g, productive rate 68.7%.
MS(ESI，m/z)：485.9[M+H] +。
Embodiment 19
Tablet containing promoting agent I-1:
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mixes, add polyvinylpyrrolidonesolution solution, mixing, softwood processed, sieves, wet granular processed, in 50-60 DEG C of drying, sieves Sodium carboxymethyl starch, Magnesium Stearate and talcum powder and is added to compression molding in above-mentioned particle.
Empirical tests, above-mentioned composition also has good promotion glucose in urine and discharges hypoglycemic activity in effect and body.

Claims (8)

1. the compound of general formula (I) and pharmaceutically acceptable ester:
Wherein,
R 1, R 2be selected from respectively: H, F, Cl, C 1~ C 5alkyl, C 1~ C 5alkoxyl group ,-O-aryl ,-OC 1-5-aryl, cycloalkyl;
Or R 1and R 2form cycloalkyl or there is 1-4 together with the carbon atom that they connect and be selected from N, O, S, SO and/or SO 2the replacement of heteroatomic 5-12 unit or unsubstituted aromatic heterocycle;
Wherein, described cycloalkyl, aryl, aromatic heterocycle can be replaced by one or more substituting group further, and described substituting group comprises halogen atom, hydroxyl, alkyl, the alkoxyl group that replaced by halogen atom, substituted or unsubstituted aryl or aralkyl.
2. what claim 1 defined has the compound of general formula (I) and pharmaceutically acceptable ester:
Wherein R 1preferably certainly: C 1~ C 5alkyl, C 1~ C 5alkoxyl group;
R 2preferably certainly: F, Cl, C 1~ C 5alkyl;
Or R 1and R 2formed together with the carbon atom that they connect and there is 1-4 be selected from N, O, S, SO and/or SO 2the replacement of heteroatomic 5-12 unit or unsubstituted aromatic heterocycle;
Wherein, described aromatic heterocycle can be replaced by one or more substituting group further, and described substituting group comprises halogen atom, hydroxyl, alkyl, alkoxyl group, the alkoxyl group that replaced by halogen atom, substituted or unsubstituted aryl or aralkyl.
3. what claim 2 defined has the compound of general formula (I) and pharmaceutically acceptable ester:
Wherein R 1preferably certainly: methoxyl group, oxyethyl group, propoxy-;
R 2preferably certainly: F, Cl, methyl, ethyl;
Or R 1and R 2the replacement of 5 yuan with 1 Sauerstoffatom or unsubstituted aromatic heterocycle is formed together with the carbon atom that they connect.
4. general formula (I) compound that defines of claim 3 and pharmaceutically acceptable ester, described compound is selected from:
The chloro-3-of 4-(4-oxyethyl group-3-luorobenzyl) benzene-1-base-β-D-glucopyranoside;
The chloro-3-of 4-(4-oxyethyl group-3-chlorobenzyl) benzene-1-base-β-D-glucopyranoside;
The chloro-3-of 4-(4-oxyethyl group-3-methyl-benzyl) benzene-1-base-β-D-glucopyranoside;
The chloro-3-of 4-(diphenylene-oxide-2-methyl) benzene-1-base-β-D-glucopyranoside;
The chloro-3-of 4-(2-ethoxymethyl cumarone-5-methyl) benzene-1-base-β-D-glucopyranoside;
The chloro-3-of 4-(2-benzyloxymethyl cumarone-5-methyl) benzene-1-base-β-D-glucopyranoside;
The chloro-3-of 4-(2-(2-tetrahydrofuran (THF) methoxyl methyl) cumarone-5-methyl) benzene-1-base-β-D-glucopyranoside;
The chloro-3-of 4-(4-oxyethyl group-3-luorobenzyl) benzene-1-base-6-O-methoxycarbonyl-β-D-glucopyranoside.
5. the synthetic method of general formula (I) compound that defines of claim 1-4, comprises the following steps:
Formula II compound reacts with lactone II I with after n-Butyl Lithium process, obtains formula IV compound; Use triethyl silicane and boron trifluoride diethyl etherate reduction-type IV compound again, can V compound for the preparation, through full acetylated, and split preparation formula VI compound through recrystallization, then be hydrolyzed to obtain formula I through LiOH; Wherein R 1preferably certainly: methoxyl group, oxyethyl group, propoxy-; R 2preferably certainly: F, Cl, methyl, ethyl; Or R 1and R 2the replacement of 5 yuan with 1 Sauerstoffatom or unsubstituted aromatic heterocycle is formed together with the carbon atom that they connect.
6. the synthesis step of general formula (I) compound that defines of claim 1-4 pharmaceutically acceptable ester:
The R of Compound I monovalent 3cOCl process, esterification on the 6-O position of the glucose fragment of Compound I, the pharmaceutically acceptable ester of general formula (I) compound that obtained this claim 1-4 defines; Wherein, R 3be selected from the pharmaceutically acceptable group such as Me, Et, MeO and EtO, preferred MeO and EtO.
7. general formula (I) compound that claim 1-4 defines is preventing or is treating the application in diabetes.
8. a pharmaceutical composition, general formula (I) compound containing one of claim 1-4 and suitable carrier or vehicle.
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