CN103772449A - C-aryl glucoside derivative as well as preparation method and application thereof - Google Patents

C-aryl glucoside derivative as well as preparation method and application thereof Download PDF

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CN103772449A
CN103772449A CN201210417566.5A CN201210417566A CN103772449A CN 103772449 A CN103772449 A CN 103772449A CN 201210417566 A CN201210417566 A CN 201210417566A CN 103772449 A CN103772449 A CN 103772449A
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phenyl
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CN103772449B (en
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陈友喜
付小旦
刘亦斌
代永智
郜飞
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Nanjing Changao Pharmaceutical Science and Technology Co Ltd
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Shanghai Sun Sail Pharmaceutical Science and Technology Co Ltd
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Abstract

The invention discloses a C-aryl glucoside derivative shown in the general formula (I) (refer to the Specification), as well as a preparation method and application thereof, wherein R1 and R2 are defined in the Specification. The C-aryl glucoside derivative is novel in structure, has very strong inhibitory activity to SGLT-2, and is higher in selection ratio of SGLT-1 and SGLT-2, can be used for preparing drugs for treating and preventing diseases related to sodium-glucoseco-transporter.

Description

C-aryl glucoside derivative and preparation method thereof and purposes
Technical field
The invention belongs to pharmacology, pharmaceutical chemistry and area of pharmacology, particularly relate to class novel C-aryl glucoside derivative, the preparation method of this compounds and the application in the medicine of preparation treatment and sodium dependent glucose transport protein 2 (sodium-glucoseco-transporter 2, SGLT-2) relative disease thereof.
Background technology
Type ii diabetes is a kind of non insulin dependent diabetes, there is sensitive organization causes hyperglycemia feature [American Diabetes Association:Standards of medicalcare in diabetes2008.Diabetes Care to insulin replies failure and B cell dysfunction, 2008,31, Suppl 1, S12 – S54].In November, 2010, the investigation discovery that diabetes mellitus in China association is up-to-date, the diabetics of China approaches 100,000,000, and surmounting India becomes diabetes the first big country, more than 90% is wherein type ii diabetes.
At present conventional treatment diabetes medicament comprises the DPPIV inhibitor sitagliptin of sulfonylurea, biguanides, euglycemic agent (row ketone), non-sulfonylurea Drugs Promoting Insulin Secretion (how be listed as class), alpha-glucosidase inhibitor and listing recently etc.All these antidiabetic medicines all have limitation separately: the common adverse reactions of sulfonylureas is that gastric acid secretion increases, feels sick and hypoglycemic reaction is more easily occurred other class oral antidiabetic drug to, biguanides main adverse reaction is gastrointestinal reaction and lactic acidosis, euglycemic agent is mainly liver toxicity, alpha-glucosidase inhibitor can cause belly flatulence and diarrhea, and DPPIV inhibitor needs and N1,N1-Dimethylbiguanide share and just can reach desirable hypoglycemic effect.
The focus of international diabetes annual meeting in 2009 is 2 type sodium glucose transporters (SGLT-2).Healthy human body exceedes 99% blood sugar and reuptakes blood back liquid after by glomerular filtration, is excreted in urine less than 1% blood sugar, and this process completes by sodium dependent glucose transporter (SGLT-1/2).The wherein SGLT-2 of low-affinity, high turn-over capacity, is mainly distributed in kidney, completes 90% glucose in urine and heavily absorbs [J.Med.Chem.2008,51,1145-1149].Now there are some researches show, when SGLT-2 inhibitor hypoglycemic, do not put on weight, can not cause hypoglycemia [Expert Opin.Pharmacother, 2009,10 (15), 2527-2535].Can stop renal glomerulus blood sugar to be reuptaked and suppress SGLT-2, unnecessary blood sugar is drained in urine, thereby reduce diabetics's blood sugar, greatly alleviate the infringement to target organ under hyperglycemia state.And the SGLT-1 of high-affinity, low turn-over capacity is mainly distributed in stomach, heart and kidney (completing 10% glucose in urine heavily absorbs); suppressing SGLT-1 can cause as serious negative consequence [Nature such as hereditary syndrome glucose/semi-lactosi malabsorptions (GGM); 1991; 350 (6316), 354-356; Biochim Biophys Acta, 2001,1536,141-147].
Improve compound and not only can improve hypoglycemic effect in chemical combination object for the selection ratio of SGLT1/SGLT2, and significant for drug safety.So we when how research improves SGLT-2 inhibitor activity, also need emphasis to consider to improve the selection ratio of compound for SGLT1/SGLT2.
SGLT-2 inhibitor has become the most fruitful field of the current antidiabetic medicine of development of new in the world, many major companies and institutions for academic research are all actively developed 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 this field is at present first SGLT-2 inhibitor medicaments dapagliflozin of Bristol Myers Squibb and the common research and development of AstraZeneca.This medicine goes on the market in European Union in March, 2012.
In the process of finding at dapagliflozin; the researchist of 100 o'clock Mei-Shi Guibao finds; inhibition activity, the SGLT-1/SGLT-2 selectivity impact of R substituting group on end phenyl ring on SGLT-2 is very large; by screening different R groups; and in conjunction with former work, within 100 o'clock, Mei-Shi Guibao company has found this candidate compound of dapagliflozin [Bioorg Med Chem Lett, 2008; 18,4770-4773; Journal of Medicinal Chemistry, 2008,51,1145-1149].
Different companies all transforms the R substituting group of this phenyl ring, has also all obtained some good result [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.].Different experimental result demonstrations, the substituent variation of R, to the improvement of compound activity and metabolism situation, has vital impact.
Meanwhile, Pfizer finds, the oxo bridge ring in different bglii fragment in dapagliflozin molecule head position and 5 increases is connected, inhibition activity, the SGLT-1/SGLT-2 selectivity of SGLT-2 all greatly improve [Bioorg.Med.Chem.Lett., 2010,20,1569-1572].
Literature value: IC 50(h-SGLT2)=0.88nM
IC 50(h-SGLT1)＝1960nM
Summary of the invention
The object of the present invention is to provide a class to there is very C-aryl glucoside derivative or its optical isomer of strong inhibitory activity, fine SGLT-1/SGLT-2 selection ratio, their Preparation method and use to SGLT-2.
In a first aspect of the present invention, provide the compound shown in a kind of general formula (I) or its optical isomer:
Figure BDA00002313195600032
Wherein:
R 2be selected from: hydrogen, chlorine or methyl;
Y is selected from: C=C or S;
R 1be selected from:
Figure BDA00002313195600033
Figure BDA00002313195600034
Wherein, R 3be selected from: hydrogen, fluorine, chlorine, bromine, methyl or trifluoromethyl.
There are multiple unsymmetrical carbons in the compounds of this invention, therefore, shown in formula (I), compound comprises single enantiomer, non-enantiomer mixture, racemic modification and single diastereomer.
In the compound of general formula (I), title and the structural formula of the preferred compound of part are as shown in table 1.
Table 1 representative compound of the present invention
Figure BDA00002313195600035
Figure BDA00002313195600041
Figure BDA00002313195600051
In a second aspect of the present invention, provide the preparation method of the compounds of this invention.
Compound of the present invention can be prepared by reaction process and description below:
Flow process 1:
Figure BDA00002313195600052
As shown in flow process 1, in polar aprotic solvent, 5-reductive agent reduction such as dimethyl sulphide borine for bromo-2-chloro-benzoic acid, obtain intermediate a.
Intermediate a is at 0～-78 ℃, in polar aprotic solvent, and under highly basic exists, with DMF(dimethyl formamide) react and obtain intermediate b; Polar aprotic solvent can be selected from: toluene, dimethylbenzene, benzene, tetrahydrofuran (THF), ether, methyl tert-butyl ether, Isosorbide-5-Nitrae-dioxane; Highly basic can be selected from: n-Butyl Lithium, isobutyl-lithium, tert-butyl lithium, trityl group lithium; Optimum condition is :-40 ℃～-78 ℃, take tetrahydrofuran (THF) as solvent, make alkali with n-Butyl Lithium, reaction 1-3 hour.
At 0～60 ℃, in polar aprotic solvent, under Louis acid catalysis, intermediate b and dithioglycol reaction obtain intermediate c.Polar aprotic solvent can be selected from: methylene dichloride, chloroform, 1,2-ethylene dichloride; Lewis acid can be selected from: aluminum chloride, zinc dichloride, boron trifluoride diethyl etherate, iron trichloride, tin tetrachloride, titanium tetrachloride; Optimum condition is: take methylene dichloride as solvent, boron trifluoride diethyl etherate is catalyzer, room temperature reaction 10-24 hour.
At 0～60 ℃, in polar aprotic solvent, under the existence of alkali, allyl group halides and c reaction obtain the intermediate d of allyl group protection.Polar aprotic solvent can be selected from: DMF, dimethyl sulfoxide (DMSO) (DMSO), acetonitrile; Allyl group base halides can be selected from: allyl bromide 98, chlorallylene; Alkali can be selected from: sodium hydride, salt of wormwood, sodium carbonate, triethylamine, diisopropyl ethyl amine; Optimum condition is: take DMF as solvent, add allyl bromide 98 and sodium hydride, room temperature reaction 10-24 hour.
At 0～-90 ℃, in polar aprotic solvent, under the existence of highly basic, (its building-up process is referring to Journal of the Chemical Society for intermediate d and e, Perkin Transactions 1:Organic and Bio-Organic Chemistry (1972-1999), (1), 21-6; 1987) reaction obtains intermediate f.Polar aprotic solvent can be selected from: toluene, dimethylbenzene, benzene, tetrahydrofuran (THF), ether, methyl tert-butyl ether, Isosorbide-5-Nitrae-dioxane; Highly basic can be selected from: n-Butyl Lithium, isobutyl-lithium, tert-butyl lithium, trityl group lithium; Optimum condition is :-78 ℃, take tetrahydrofuran (THF) as solvent, make alkali with n-Butyl Lithium, reaction 1-5 hour.
At 0～90 ℃, in polar aprotic solvent, the reaction of intermediate f and fluorination reagent, obtains intermediate g after sloughing protecting group.Polar aprotic solvent can be selected from: tetrahydrofuran (THF), ether, methyl tert-butyl ether, Isosorbide-5-Nitrae-dioxane; Fluorination reagent can be selected from: tetra-n-butyl Neutral ammonium fluoride (TBAF), hydrofluoric acid pyridinium salt (PPHF); Optimum condition is: take tetrahydrofuran (THF) as solvent, add tetra-n-butyl ammonium fluoride solution, room temperature reaction 0.5-5 hour.
At 0～120 ℃, in polar protic solvent, under the existence of alkali, intermediate g and formaldehyde reaction obtain intermediate h.Polar protic solvent can be selected from: methyl alcohol, ethanol and C 3-C 4simple alcohols; Alkali can be selected from: salt of wormwood, sodium carbonate, cesium carbonate, Quilonum Retard; Optimum condition is: take methyl alcohol as solvent, add formaldehyde and salt of wormwood, 70 ℃-90 ℃ reaction 10-30 hour.
At-20～60 ℃, in polar aprotic solvent, with sodium borohydride reduction intermediate, h generates intermediate i.This reaction, at 0 ℃-30 ℃ reaction 2-8 hour, reacts completely.Except sodium borohydride, also can be with other reductive agent, as: lithium aluminium hydride, sodium borohydride-boron trifluoride diethyl etherate, sodium borohydride-aluminum chloride or sodium borohydride-titanium tetrachloride.
At 20～60 ℃, take water as solvent, under protonic acid exists, intermediate i closes ring and obtains intermediate j.Protonic acid can be selected from: trifluoracetic acid, acetic acid, formic acid; Optimum condition is: substrate is dissolved in CF 3cOOH:H 2o=9:1(volume ratio) solution in, room temperature reaction 2-4 days.
At-20～60 ℃, in polar aprotic solvent, under the existence of alkali, intermediate j reacts with acetylation reagent, obtains full acetylated intermediate k.Polar aprotic solvent can be selected from: methylene dichloride, chloroform, 1,2-monochloroethane; Acetylation reagent can be selected from: Acetyl Chloride 98Min., diacetyl oxide; Organic bases can be selected from: triethylamine, diisopropyl ethyl amine (DIPEA), DMAP; Optimum condition is: room temperature, make alkali with DMAP, DIPEA, and methylene dichloride is solvent, adds diacetyl oxide, room temperature reaction 10-20 hour.
At 20～120 ℃, in the mixed solvent of polar protic solvent and water, under the existence of alkali, intermediate k reacts with palladium reagent, obtains intermediate l.Polar protic solvent is selected from: acetic acid, trifluoracetic acid, formic acid; Palladium reagent can be selected from: Palladous chloride, palladium; Alkali can be selected from: sodium-acetate, sodium carbonate, salt of wormwood; Optimum condition is: compound k is dissolved in to Glacial acetic acid: water=9:1(volume ratio) solution, add palladium chloride, sodium acetate, 60 ℃-80 ℃ reaction 2-5h.
At 20～60 ℃, in polar aprotic solvent, under the existence of brominated reagent, intermediate l bromo obtains intermediate m.Polar aprotic solvent is selected from: methylene dichloride, chloroform, 1,2-monochloroethane.Brominated reagent is selected from NBS-triphenylphosphine system, phosphorus tribromide.Optimum condition is: compound l is dissolved in to methylene dichloride, adds NBS-triphenylphosphine, room temperature reaction 2-6h.
Flow process 2:
As shown in flow process 2, at 20～160 ℃, in polar aprotic solvent, bromide reacts and obtains tin reagent intermediate with palladium reagent, tin reagent.Polar aprotic solvent can be selected from: toluene, dimethylbenzene, benzene, tetrahydrofuran (THF), ether, methyl tert-butyl ether, Isosorbide-5-Nitrae-dioxane; Palladium reagent can be selected from tetra-triphenylphosphine palladium, dichloro two triphenylphosphine palladium triphenylphosphine systems; Tin reagent is selected from six normal-butyl tin ethers, tri-n-butyltin chloride.Optimum condition, for bromide is dissolved in to toluene, adds Pd (PPh 3) 4and Bu 3sn-SnBu 3, 80 ℃-140 ℃ reaction 5-15h.
Flow process 3:
Figure BDA00002313195600081
As shown in flow process 3, at 20～160 ℃, in polar aprotic solvent, under the effect of alkali and palladium reagent, there is stille linked reaction in intermediate iii and tin reagent intermediate, obtains coupled product.Polar aprotic solvent can be selected from: Isosorbide-5-Nitrae-dioxane, DMF (DMF), toluene, DMSO, glycol dimethyl ether (DME); Alkali can be selected from: salt of wormwood, sodium carbonate, potassiumphosphate, cesium carbonate.Palladium catalyst can be selected from: PdCl 2(PPh 3) 2-PPh 3, Pd (PPh 3) 4; Optimum condition is: take Isosorbide-5-Nitrae-dioxane as solvent, salt of wormwood is made alkali, Pd (PPh 3) 4for catalyzer, 80-140 ℃ of reaction 5-15 hour.
At 0～100 ℃, in polar protic solvent, under the effect of alkali, coupled product deprotection base, obtains formula (I) compound.Polar protic solvent can be selected from: water-tetrahydrofuran (THF), methyl alcohol, ethanol; Alkali can be selected from: salt of wormwood, sodium carbonate, sodium hydroxide, lithium hydroxide, sodium methylate, sodium ethylate.Optimum condition is: take methyl alcohol as solvent, sodium methylate is made alkali, regulates pH=11, room temperature reaction 0.1-5 hour.
In a third aspect of the present invention, provide the purposes of arbitrary compound noted earlier, for the preparation of the medicine for the treatment of or prevent diabetes, obesity and other and sodium dependent glucose translocator (SGLT-2) relative disease.
Major advantage of the present invention is: the C-aryl glucoside derivative shown in general formula of the present invention (I) or its optical isomer are the SGLT-2 inhibitor of a class recruit structure, they have the active and excellent drug metabolism character of very strong inhibition and good security to SGLT-2, glucose in urine discharge for animal has obvious promoter action, is particularly suitable as SGLT-2 inhibitor and is used for the treatment of the disease that diabetes, obesity etc. are relevant to SGLT-2.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be appreciated that these embodiment, only for the present invention is described, limit the scope of the invention and be not used in.The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise umber and per-cent are weight part and weight percent.
In all embodiment, thermometer is not proofreaied and correct; 1varian Mercury 400 nuclear magnetic resonance analyser records for H-NMR, chemical shift represents with δ (ppm); Shimadzu LC-MS-2020 mass spectrograph for the mensuration of MS.Separate with the undeclared 200-300 order that is of silica gel, the proportioning of elutriant is volume ratio.
Embodiment 1 (1S, 2S, 3S, 4R, 5S)-5-(the chloro-3-of 4-(4-(DHF-3-yl) benzyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2, the preparation of 3,4-triol (compound 1)
(formula a) for the synthetic bromo-2-chlorobenzyl alcohol of 5-of step 1.
Figure BDA00002313195600091
Chloro-2-5-bromo-benzoic acid (4.0g, 0.0170mol) is dissolved in anhydrous tetrahydro furan (24ml) to argon shield; at 0 ℃, be added dropwise to dimethyl sulphide borine (8.7ml; 0.0849mol), room temperature reaction 5 hours afterwards, TLC(thin-layer chromatography) monitor to reacting completely; ice-water bath; slowly drip water, ethyl acetate extraction, is spin-dried for; obtain 3.6g white solid, crude product directly drops into next step.
(formula b) for the synthetic chloro-3-methylol of the 4-phenyl aldehyde of step 2.
Figure BDA00002313195600092
Under argon shield; by compound a (2.2g; 0.01mol) be dissolved in 20ml THF(tetrahydrofuran (THF)) in, be cooled to-78 ℃, drip n-Butyl Lithium (8ml; 0.02mol); insulation reaction 1h, drips DMF (11.5ml, 0.15mol); insulation reaction 1h; TLC monitors to reacting completely, and with saturated ammonium chloride cancellation reaction, is extracted with ethyl acetate; organic phase is water, saturated common salt water washing successively; dry, filter, be spin-dried for; column chromatography obtains white solid (716mg, 42%).LC-MS:193.0[M+Na] +。
(formula c) for methyl alcohol for step 3. synthetic (the chloro-5-of 2-(1,3-sulphur-2-yl) phenyl)
Figure BDA00002313195600093
Compound b (710mg, 4.16mmol) is dissolved in 15ml DCM, adds 1,3-dimercaptopropane (1.3ml, 12.49mmol), drips boron trifluoride diethyl etherate (1.6ml under ice bath, 12.49mmol), room temperature reaction, LCMS detects, under ice bath, be adjusted to alkalescence with 1N sodium hydroxide, DCM(methylene dichloride) extraction, organic phase is water, saturated common salt water washing successively, dry, filter, be spin-dried for, column chromatography obtains white solid (420mg, 40%).
1H NMR(400MHz，CDCl 3):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. is synthesized (2-(3-propylene oxygen methyl)-4-chlorobenzene)-1, and (compound d) for 3-dithian
Figure BDA00002313195600101
Compound c (2.13g, 8.17mmol) is dissolved in 20ml THF, adds sodium hydride (390mg at 0 ℃ in batches, 9.8mmol), room temperature reaction 30min, drips allyl bromide 98 (1ml, 12.2mmol), room temperature reaction 2h, TLC monitors to reacting completely, reaction solution is poured in frozen water, be extracted with ethyl acetate, organic phase is water, saturated common salt water washing successively, dry, filter, be spin-dried for, column chromatography obtains yellow liquid (1.67g, 68%).
1H NMR(400MHz,CDCl 3):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. is synthesized (R)-(2-(3-propylene oxygen methyl)-4-chloro-phenyl--1,3-bis-sulphur-2-yl)-((3as, 4R, 6R, 6aS)-6-(tertiary butyl dimethyl-silicon)-O-)-2, (formula f) for 2-dimethyl furan-[3,4-d] [1,3]-Er Evil-4-methyl alcohol
Under argon shield, by compound d (12.22g, 40.6mmol) be dissolved in the anhydrous THF of 100ml, be chilled to-78 ℃, be added dropwise to n-BuLi (18ml, 46mmol), drip and finish, insulation reaction 1.5 hours, Ar protection, by Verbindung (12.3g, 40.6mmol) be dissolved in 100mlTHF, be chilled to-78 ℃, above-mentioned reaction solution is added wherein, insulation reaction 1 hour, allow it naturally be warming up to-20 ℃, TLC detects a small amount of raw material, under ice bath, add saturated ammonium chloride solution, add water, EA(ethyl acetate) extraction, organic phase is water successively, saturated sodium-chloride is washed, anhydrous magnesium sulfate drying, filter, be spin-dried for, obtain faint yellow oily matter 25.4g (crude product), directly drop into next step reaction.
Step 6. is synthesized (3aS, 4S, 6R, 6aS)-6-((R)-2-(3-propylene oxygen methyl-4-chloro-phenyl-)-1,3-bis-sulphur-2-yl)-methylol-2, and 2, (compound is g) for dimethyl furan [3,4-d] [1,3]-Er Evil-4-alcohol
Figure BDA00002313195600111
Above-mentioned steps 5 gained crude products (25.4g, 42.1mmol) are dissolved in 200ml THF, are chilled to 0 ℃, be added dropwise to 4-butyl ammonium fluoride trihydrate (TBAF.3H 2o, 26.6g, 84.2mmol) THF (200ml) solution, insulation reaction 15min, TLC detection reaction is complete, adds saturated ammonium chloride solution, add water, EA extraction, organic phase successively water, saturated sodium-chloride is washed, anhydrous magnesium sulfate drying, filter, be spin-dried for column chromatography, obtain white blister powder (7g, 34%).
1H NMR(400MHz,CDCl 3):δ7.93-8.05(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. is synthesized (3aS, 4S, 6R, 6aS)-6-((R)-2-(3-propylene oxygen methyl-4-chloro-phenyl-)-1,3-bis-sulphur-2-yl)-methylol-2,2, (formula h) for dimethyl furan [3,4-d] [1,3]-Er Evil-4-alcohol
Figure BDA00002313195600112
Ar protection, is dissolved in compound g (7g, 14.3mmol) in 200ml methyl alcohol; add salt of wormwood (9.9g, 71.6mmol) in formaldehyde (37%, 48.5ml; 644mmol); 85 ℃ of reactions are spent the night, and TLC detection reaction is complete, under condition of ice bath; add a small amount of methyl alcohol; with 1NHCl adjusting pH to 7, be spin-dried for, add water; EA extraction; organic phase successively water, saturated sodium-chloride is washed, and anhydrous magnesium sulfate drying filters; be spin-dried for; column chromatography, obtains white blister powder (4.43g, 60%).
1H NMR(400MHz,CDCl 3):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. is synthesized (3aS, 4S, 6R, 6aS)-6-((R)-2-(3-propylene oxygen methyl-4-chloro-phenyl-)-1,3-bis-sulphur-2-yl)-methylol-3a-methylol-2,2-dimethyl furan [3,4-d] (formula is i) for [1,3]-Er Evil-4-alcohol
Figure BDA00002313195600121
Starting compound h (4.43g, 8.53mmol) is dissolved in 40ml methyl alcohol, and ice bath is chilled to 0 ℃, adds sodium borohydride (0.323g, 8.53mmol) in batches, room temperature reaction, and in its process, each hour added the sodium borohydride of 1.0eq.LC-MS detection reaction is complete, adds saturated ammonium chloride solution, be spin-dried for, and DCM extraction, organic phase successively water, saturated sodium-chloride is washed, and anhydrous magnesium sulfate drying filters, and is spin-dried for, and obtains white powder 5.38g.Crude product directly drops into next step.
Step 9. synthesize (1R, 2R)-1-(2-(3-propylene oxygen methyl-4-chloro-phenyl-)-1,3-bis-sulphur-2-yl }-2-(5,5-bis-(methylol)-2,2-dimethyl-1,3-bis-Evil-4-) (formula is j) for-1，2-ethandiol
Compound i (5.38g, 10.3mmol) is dissolved in to 160ml CF 3cOOH:H 2o=9:1(volume ratio) solution in, room temperature reaction 4 days, LC-MS detection reaction is complete, and 1N NaOH is adjusted to alkalescence, EA extraction, organic phase successively water, saturated sodium-chloride is washed, and anhydrous sodium sulfate drying filters, be spin-dried for, obtain pale yellow powder (2.39g, 62%), directly throw next step.
Step 10. is synthesized (1S, 2S, 3S, 4R, 5S)-5-(3-propylene oxygen methyl-4-chloro-phenyl-)-1-methylol-6,8-dioxane [3,2,1] octane-2, and (formula is k) for 3,4-triol
Figure BDA00002313195600131
By compound j (2.37g, 6.36mmol) be dissolved in 30ml DCM, add DMAP (DMAP, 39mg, 0.32mmol), N, N-diisopropylethylamine (DIPEA, 8.1ml, 46.43mmol), under ice bath, drip diacetyl oxide (4ml, 41.98mmol), room temperature reaction 18h, TLC detection reaction.The cancellation that adds water under ice bath reaction, with DCM extraction, organic phase washing, saturated sodium-chloride is washed, and anhydrous sodium sulfate drying filters, and is spin-dried for, and column chromatography obtains yellow powder (986mg, 29%).
1H NMR(400MHz,CDCl 3):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. is synthesized (1R, 2S, 3S, 4R, 5S)-1-(acetyl-o-methyl)-5-(3-[-propylene oxygen methyl-4-chloro-phenyl-]-6,8-dioxane [3,2,1] octane)-2,3, and (formula l) for 4-tri-base triacetates
Figure BDA00002313195600132
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) mix, 70 ℃ of reaction 3h, TLC detects, and cooling reaction solution filters, filtrate adds water, be extracted with ethyl acetate, organic phase is used saturated sodium bicarbonate, saturated common salt water washing successively, dry, filter, revolve and desolventize, obtain yellow oil (2.05g, 80%).LC-MS:523.1[M+Na] +。
Step 12. is synthesized (1R, 2S, 3S, 4R, 5S)-1-(acetoxy-methyl)-5-(the chloro-3-of 4-(methylol) phenyl)-6, and 8-dioxa two encircles [3.2.1] octane-2, and (formula m) for 3,4-, tri-base triacetates
Figure BDA00002313195600141
By compound l (2.05g, 4.09mmol) be dissolved in 20ml methylene dichloride, under ice bath, add n-bromo-succinimide (NBS, 0.875g, 4.91mmol), add triphenylphosphine (1.3g in batches, 4.91mmol), room temperature reaction spends the night, and TLC detects, be spin-dried for column chromatography.Obtain yellow solid (1.315g, 57%).
1H NMR(400MHz,CDCl 3)δ7.59-7.60(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. is synthesized the bromo-4-isoolefine of 1-propylbenzene (formula 1-1)
Three-necked bottle to the deacration that dewaters in advance adds Ph 3pCH 2br (29.6g, 82.9mmol), adds part THF (130ml), in ice bath, add t-BuOK (25.368g, 226.08mmol), reaction 1h in batches, parabromoacetophenone is dissolved in remaining 20ml THF and adds reaction flask, 75 ° of C backflow reaction overnight.Next day, TLC monitoring is to after reacting completely, to the cancellation reaction that adds water in reaction system, EA extraction, organic phase saturated common salt water washing, anhydrous Na 2sO 4dry, filter, vacuum desolventizing, residue obtains transparent liquid (10.473g, 70.5%) through rapid column chromatography purifying (sherwood oil).LC-MS:219.0[M+Na] +。
Step 14. is synthesized the bromo-4-of 1-(3-bromine isoolefine propyl group) benzene (formula 1-2)
Under Ar protection, n-bromo-succinimide (NBS, 10.2g, 57.09mmol) good to compound 1-1 (7.5g, 38.06mmol) and recrystallization is dissolved in to 95ml CHCl 3in, be heated to 75 ° of C backflow reaction overnight.Next day, TLC monitoring is to after reacting completely, filtering insolubles, and solvent evaporated, then wash with sherwood oil, adularescent solid is separated out, and filters out, and filtrate, except desolventizing, is directly dropped into next step.
Step 15. is synthesized 1-(3-allyloxy-isoolefine propyl group)-4-bromobenzene (formula 1-3)
Figure BDA00002313195600151
In dry three-necked bottle, add successively compound 1-2 (9.6g, 34.8mmol), 2-propylene-1-alcohol (3.03g, 52.2mmol) and THF (100m), stirring reaction in ice bath, then add NaH (2.784g in batches, 69.6mmol), ambient temperature overnight reaction.Next day, TLC monitoring is to after reacting completely, and rapid column chromatography purifying (sherwood oil: ethyl acetate=50:1), obtains yellow colloid (3.996g, 45%).LC-MS:275.0[M+Na] +。
Step 16. is synthesized 3-(4-bromophenyl)-2,5-dihydro-tetrahydrofuran (THF) (formula 1-4)
Figure BDA00002313195600152
Under Ar protection, compound 1-3 (3.99g, 15.76mmol) and Grubbs II (267mg, 0.315mmol) are dissolved in to 200ml CH 2cl 2in, be heated to 45 ° of C back flow reaction and spend the night.Next day, after TLC reacts completely, rapid column chromatography purifying (sherwood oil: ethyl acetate=50:1), vacuum is removed solvent, obtains white solid (1.207g, 34%).
1H NMR(400MHz,CDCl 3)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. is synthesized 2-(4-tributyl tin phenyl) furans (formula 1-5)
Figure BDA00002313195600153
In dried in advance three-necked bottle, add compound 1-4 (500mg, 2.07mmol), Pd (PPh 3) 4(159mg, 0.138mmol), Bu 3sn-SnBu 3(3.196g, 5.51mmol), heavily steam toluene 15ml, under argon shield in 100 ℃ of backflow reaction overnight.Next day, after TLC reacts completely, remove solvent, rapid column chromatography (in the solvent of first using sherwood oil: triethylamine=100:1 and silica gel with rush post, then rush post, sherwood oil with 1.5L sherwood oil: ethyl acetate=50:1), obtain product 157mg.Directly drop into next step.
Step 18. is synthesized (1S, 2S, 3S, 4R, 5S)-1-(acetoxy-methyl)-5-(the chloro-3-of 4-(DHF-3-yl) benzyl) phenyl)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-, tri-base triacetates (formula 1-6)
After being processed, three-necked bottle anhydrous and oxygen-free is cooled to room temperature; under argon shield; by compound 1-5 (400mg; 0.709mmol), compound m (340mg; 0.78mmol), salt of wormwood (196mg; 1.418mmol), molecular sieve adds in 20ml toluene; stirring at room temperature 30min, adds four triphenyl phosphorus palladiums (82mg, 0.0709mmol); after back flow reaction is spent the night; add filtered through silica gel reaction solution, be spin-dried for, column chromatography; obtain white solid (140mg, 32%).LC-MS:623.2[M+Na] +。
Step 19. is synthesized (1S, 2S, 3S, 4R, 5S)-5-(the chloro-3-of 4-(4-(DHF-3-yl) benzyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-triol (compound 1)
Figure BDA00002313195600162
Compound 1-6 (70mg, 0.111mmol) is dissolved in the methanol solution of sodium methylate of pH=11, room temperature reaction 30min, TLC detects, slowly add acidic resins, regulate reaction solution to neutral, suction filtration, is spin-dried for, column chromatography, obtains white solid (22mg, 40%).LC-MS:483.2[M+Na] +。
1H NMR(400MHz,CD 3OD)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 (THF)-3-yl) benzyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2, the preparation of 3,4-triol (compound 2)
Figure BDA00002313195600171
Prepare compound 2 by method similar to Example 1.Wherein, step 1-12 is with embodiment 1.
Step 13. is synthesized 2-(4-bromophenyl)-ethyl succinate (formula 2-1)
Figure BDA00002313195600172
Under argon shield; will be to bromo-acid ethyl ester (6.08g; 0.025mol) be dissolved in 60mlTHF, ice bath is cooled to 0 ℃, adds potassium hexamethyldisilazide (KHMDS; 27.5ml; 0.0275mol), after reaction 1h, add ethyl bromoacetate (2.8ml, 0.025mol); after room temperature reaction 2h, TLC detects.With saturated ammonium chloride cancellation reaction, ethyl acetate extraction, organic phase is water, saturated common salt water washing successively, and anhydrous sodium sulfate drying filters, and is spin-dried for, and column chromatography, obtains yellow oil (6.5g, 79%).
Step 14. is synthesized 2-(4-bromophenyl)-Isosorbide-5-Nitrae butyleneglycol (formula 2-2)
Compound 2-1 (340mg, 1.03mmol) is dissolved in THF (5ml heavily steams), is cooled to 0 ℃, add NaBH in batches 4(78mg, 2.07mmol), and then drip BF 3et 2o (0.26ml, 2.07mmol).After adding, rise to room temperature reaction 3h.LCMS detects, and reacts completely, and is cooled to 0 ℃, adds 1NNaOH cancellation, EA(ethyl acetate) extraction, water with EA extraction twice, merges organic phase again, uses brine(saturated aqueous common salt) dewater, anhydrous Na SO 4dry 30min.Filter, be spin-dried for, obtain yellow oil (267mg, 100%).
1H NMR(400MHz,CDCl 3)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. is synthesized 4-(4-bromophenyl)-3-1H-pyrans (formula 2-3)
Figure BDA00002313195600181
By compound 2-2 (230mg, 0.938mol) be dissolved in 5mlTHF, under ice bath, add sodium hydride (38mg, 0.938mol), after reaction 30min, add Tosyl chloride (179mg, 0.938mol), after room temperature reaction 1h, add again sodium hydride (38mg, 0.938mol), TLC detection reaction after reaction 1h.Reaction solution is poured in frozen water, be extracted with ethyl acetate, use saturated common salt water washing, anhydrous sodium sulfate drying, filters, and is spin-dried for, and column chromatography, obtains yellow oil (70mg, 33%).
1H NMR(400MHz,CDCl 3)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. is synthesized 2-(4-tributyl tin phenyl) furans (formula 2-4)
Figure BDA00002313195600182
Operation is with the step 17 in embodiment 1, and difference is that the amount of the compound 2-3 that adds is 500mg(2.07mmol), obtain product 178mg.
Step 17. is synthesized (1S, 2S, 3S, 4R, 5S)-1-(acetoxy-methyl)-5-(the chloro-3-of 4-(4-(tetrahydrofuran (THF)-3-yl) benzyl) phenyl)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-, tri-base triacetates (formula 2-5)
Figure BDA00002313195600183
Operation is with the step 18 in embodiment 1, and difference is that the amount of the compound 2-4 that adds is 341mg(0.78mmol), obtain white solid product (163mg, 42%).LC-MS:653.2[M+Na] +。
Step 18. is synthesized (1S, 2S, 3S, 4R, 5S)-5-(the chloro-3-of 4-(4-(tetrahydrofuran (THF)-3-yl) benzyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-triol (compound 2)
Operation is with the step 19 in embodiment 1, and difference is that the amount of the compound 2-5 that adds is 38mg(0.060mmol), obtain final product white solid (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-yl) benzyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2, the preparation of 3,4-triol (compound 3)
Figure BDA00002313195600192
Prepare compound 3 by method similar to Example 1.Wherein, step 1-12 is with embodiment 1.
Step 13. is synthesized tributyl (4-(3,6-dihydro-2H-pyrans-4-yl) phenyl) stannane (formula 3-2)
Figure BDA00002313195600193
Operation is with the step 17 in embodiment 1, and difference is that the consumption of compound 3-1 is 500mg(2.07mmol), Pd (PPh 3) 4consumption be 120mg(0.104mmol), Bu 3sn-SnBu 3consumption be (2.41g, 4.15mmol).
Wherein, the preparation method of compound 3-1 is referring to U.S. Pat 2011092501.
Step 14. is synthesized (1S, 2S, 3S, 4R, 5S)-1-(acetoxy-methyl)-5-(the chloro-3-of 4-(4-(3,6-dihydro-2H-pyrans-4-yl) benzyl) phenyl)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-, tri-base triacetates (formula 3-3)
Operation is with the step 18 in embodiment 1, and difference is that the consumption of compound 3-2 is 350mg(0.78mmol), obtain product white solid (225mg, 45%).LC-MS:665.2[M+Na] +。
Step 15. is synthesized (1S, 2S, 3S, 4R, 5S)-5-(the chloro-3-of 4-(4-(3,6-dihydro-2H-pyrans-4-yl) benzyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-triol (compound 3)
Figure BDA00002313195600202
Operation is with the step 19 in embodiment 1, and difference is that the consumption of compound 3-3 is 22mg(0.060mmol), obtain final product white solid (11mg, 70%).LC-MS:497.2[M+Na] +。
1H NMR(400MHz,CD 3OD)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 (THF)-2-yl) benzyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2, the preparation of 3,4-triol (compound 4)
Figure BDA00002313195600211
Prepare compound 4 by method similar to Example 1.Wherein, step 1-12 is with embodiment 1.
Step 13. is synthesized 2-(4-tributyl tin phenyl) tetrahydrofuran (THF) (formula 4-2)
Figure BDA00002313195600212
Operation is with the step 17 in embodiment 1, and difference is that the consumption of compound 4-1 is 617mg (2.76mmol), Pd (PPh 3) 4consumption be 159mg(0.138mmol), Bu 3sn-SnBu 3consumption be 3.196g (5.51mmol), obtain product 124mg.
Wherein, the preparation method of compound 4-1 is referring to U.S. Pat 4868344.
Step 14. is synthesized (1S, 2S, 3S, 4R, 5S)-1-(acetoxy-methyl)-5-(the chloro-3-of 4-(4-(tetrahydrofuran (THF)-2-yl) benzyl) phenyl)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-, tri-base triacetates (formula 4-3)
Operation is with the step 18 in embodiment 1, and difference is that the consumption of compound 4-2 is 341mg(0.78mmol), obtain product white solid (177mg, 36%).LC-MS:655.2[M+Na] +。
Step 15. is synthesized (1S, 2S, 3S, 4R, 5S)-5-(the chloro-3-of 4-(4-(tetrahydrofuran (THF)-2-yl) benzyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-triol (compound 4)
Figure BDA00002313195600214
Operation is with the step 19 in embodiment 1, and difference is that the consumption of compound 4-3 is 21mg(0.060mmol), obtain final product white solid (10mg, 63%).LC-MS:485.2[M+Na] +。
1H NMR(400MHz,CD 3OD)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-yl) benzyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2, the preparation of 3,4-triol (compound 5)
Figure BDA00002313195600221
Prepare compound 5 by method similar to Example 1.Wherein, step 1-12 is with embodiment 1.
Step 13. is synthesized tributyl (4-(tetrahydrochysene-2H-pyrans-4-yl) phenyl) stannane (formula 5-2)
Figure BDA00002313195600222
Operation is with the step 17 in embodiment 1, and difference is that the amount of the compound 5-1 that adds is 990mg (4.10mmol), Pd (PPh 3) 4amount be 237mg (0.205mmol), Bu 3sn-SnBu 3amount be (4.76g, 8.20mmol), obtain product 400mg.
Wherein, the preparation method of compound 5-1 is referring to patent WO2006106416.
Step 14. is synthesized (1S, 2S, 3S, 4R, 5S)-1-(acetoxy-methyl)-5-(the chloro-3-of 4-(4-(tetrahydrochysene-2H-pyrans-4-yl) benzyl) phenyl)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-, tri-base triacetates (formula 5-3)
Figure BDA00002313195600231
Operation is with the step 18 in embodiment 1, and difference is that the consumption of compound 5-2 is 352mg(0.78mmol), obtain product white solid (116mg, 23%).LC-MS:667.2[M+Na] +。
Step 15. is synthesized (1S, 2S, 3S, 4R, 5S)-5-(the chloro-3-of 4-(4-(tetrahydrochysene-2H-pyrans-4-yl) benzyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-triol (compound 5)
Figure BDA00002313195600232
Operation is with the step 19 in embodiment 1, and difference is that the consumption of compound 5-3 is 35mg(0.055mmol), obtain final product white solid (17mg, 66%).LC-MS:499.2[M+Na] +。
1H NMR(400MHz,CD 3OD)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-(encircle-4-of 1,3-oxa-six yl) benzyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2, the preparation of 3,4-triol (compound 6)
Figure BDA00002313195600233
Prepare compound 5 by method similar to Example 1.Wherein, step 1-12 is with embodiment 1.
Step 13. is synthesized 2-(4-tributyl tin phenyl) furans (formula 6-2)
Figure BDA00002313195600241
Operation is with the step 17 in embodiment 1, and difference is that the consumption of compound 6-1 is 1g(4.15mmol), Pd (PPh 3) 4consumption is 240mg(0.207mmol), Bu 3sn-SnBu 3consumption be 4.81g(8.29mmol), obtain product 345mg.
Wherein, the preparation method of compound 6-1 is referring to document Synthesis, 1980,11,871-872.
Step 14. is synthesized (1S, 2S, 3S, 4R, 5S)-1-(acetoxy-methyl)-5-(the chloro-3-of 4-(4-(encircle-4-of 1,3-dioxa six yl) benzyl) phenyl)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-, tri-base triacetates (formula 6-3)
Figure BDA00002313195600242
Operation is with the step 18 in embodiment 1, and difference is that the consumption of compound 6-2 is 354mg(0.78mmol), obtain product white solid (120mg, 26%).LC-MS:669.2[M+Na] +。
Step 15. is synthesized (1S, 2S, 3S, 4R, 5S)-5-(the chloro-3-of 4-(4-(encircle-4-of 1,3-dioxa six yl) benzyl) base)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-triol (compound 6)
Figure BDA00002313195600243
Operation is with the step 19 in embodiment 1, and difference is that the consumption of compound 6-3 is 20mg(0.031mmol), obtain final product white solid (8mg, 55%).LC-MS:501.2[M+Na] +。
1H NMR(400MHz,CD 3OD)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-yl)) benzyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2, the preparation of 3,4-triol (compound 7)
Figure BDA00002313195600251
Prepare compound 7 by method similar to Example 1.Wherein, step 1-12 is with embodiment 1.
Step 13. is synthesized 2-(4-tributyl tin phenyl) furans (formula 7-2)
Figure BDA00002313195600252
Operation is with the step 17 in embodiment 1, and difference is that the consumption of compound 7-1 is 989mg(4.10mmol), Pd (PPh 3) 4consumption be 237mg(0.205mmol), Bu 3sn-SnBu 3consumption be 4.76g(8.20mmol), obtain product 576mg.
Wherein, the preparation method of compound 7-1 is referring to patent WO20060125526.
Step 14. is synthesized (1S, 2S, 3S, 4R, 5S)-1-(acetoxy-methyl)-5-(the chloro-3-of 4-(4-(tetrahydrochysene-2H-pyrans-2-yl)) benzyl) phenyl)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-, tri-base triacetates (formula 7-3)
Figure BDA00002313195600253
Operation is with the step 18 in embodiment 1, and difference is that the consumption of compound 7-2 is 354mg(0.78mmol), obtain white solid (180mg, 39%).LC-MS:667.2[M+Na] +。
Step 15. is synthesized (1S, 2S, 3S, 4R, 5S)-5-(the chloro-3-of 4-(4-(tetrahydrochysene-2H-pyrans-2-yl)) benzyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-triol (compound 7)
Figure BDA00002313195600261
Operation is with the step 19 in embodiment 1, and difference is that the consumption of compound 7-3 is 40mg(0.062mmol), obtain final product white solid (17mg, 57%).LC-MS:499.2[M+Na] +。
1H NMR(400MHz,CD 3OD)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-fluorophenyl) thiophene-2-yl) methyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2, the preparation of 3,4-triol (compound 8)
Figure BDA00002313195600262
Prepare compound 8 by method similar to Example 1.Wherein, step 1-12 is with embodiment 1.
Step 13. is synthesized 2-(4-tributyl tin phenyl) furans (formula 8-2)
Operation is with the step 17 in embodiment 1, and difference is compound 8-1 (1.05mg, 4.10mmol), Pd (PPh 3) 4(237mg, 0.205mmol), Bu 3sn-SnBu 3(4.76g, 8.20mmol), obtains product 678mg.
Wherein, the preparation method of compound 8-1 is referring to patent WO2008128321.
Step 14. is synthesized (1S, 2S, 3S, 4R, 5S)-1-(acetoxy-methyl)-5-(the chloro-3-of 4-((5-(4-fluorophenyl) thiophene-2-yl) methyl) phenyl)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-, tri-base triacetates (formula 8-3)
Figure BDA00002313195600271
Operation is with the step 18 in embodiment 1, and difference is that the consumption of compound 8-2 is 367mg(0.785mmol), the consumption of compound m is 443mg(0.785mmol), obtain product white solid (291mg, 56%).LC-MS:683.1[M+Na] +。
Step 15. is synthesized (1S, 2S, 3S, 4R, 5S)-5-(the chloro-3-of 4-((5-(4-fluorophenyl) thiophene-2-yl) methyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-triol (compound 8)
Figure BDA00002313195600272
Operation is with the step 19 in embodiment 1, and difference is that the consumption of compound 8-3 is 67mg(0.101mmol), obtain final product white solid (30mg, 60%).LC-MS:515.1[M+Na] +。
1H NMR(400MHz,CD 3OD)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-(the chloro-3-of 4-((5-(4-trifluoromethyl) thiophene-2-yl) methyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2, the preparation of 3,4-triol (compound 9)
Figure BDA00002313195600273
Prepare compound 9 by method similar to Example 1.Wherein, step 1-12 is with embodiment 1.
Step 13. is synthesized 2-(4-tributyl tin phenyl) furans (formula 9-2)
Figure BDA00002313195600281
Operation is with the step 17 in embodiment 1, and difference is that the consumption of compound 9-1 is 1.26mg(4.10mmol), Pd (PPh 3) 4consumption be 237mg(0.205mmol), Bu 3sn-SnBu 3consumption be 4.76g(8.20mmol), obtain product 798mg.
Wherein, the preparation of compound 9-1 is referring to Organic Letters, and 2005 (7), 5083-5085.
Step 14. is synthesized (1S, 2S, 3S, 4R, 5S)-1-(acetoxy-methyl)-5-(the chloro-3-of 4-((5-(4-trifluoromethyl) thiophene-2-yl) methyl) phenyl)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-, tri-base triacetates (formula 9-3)
Operation is with the step 18 in embodiment 1, and difference is that the consumption of compound 9-2 is 406mg(0.785mmol), the consumption of compound m is 443mg(0.785mmol), obtain product white solid (190mg, 46%).LC-MS:733.1[M+Na] +。
Step 15. is synthesized (1S, 2S, 3S, 4R, 5S)-5-(the chloro-3-of 4-((5-(4-trifluoromethyl) thiophene-2-yl) methyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-triol (compound 9)
Figure BDA00002313195600283
Operation is with the step 19 in embodiment 1, and difference is that the consumption of compound 9-3 is 56mg(0.079mmol), obtain final product white solid (28mg, 65%).LC-MS:565.1[M+Na] +。
1H NMR(400MHz,CD 3OD)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 phenyl) thiophene-2-yl) methyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2, the preparation of 3,4-triol (compound 10)
Prepare compound 10 by method similar to Example 1.Wherein, step 1-12 is with embodiment 1.
Step 13. is synthesized 2-(4-tributyl tin phenyl) furans (formula 10-2)
Figure BDA00002313195600292
Operation is with the step 17 in embodiment 1, and difference is that the consumption of compound 10-1 is 1.03mg(4.10mmol), Pd (PPh 3) 4consumption be 237mg(0.205mmol), Bu 3sn-SnBu 3consumption be 4.76g(8.20mmol), obtain product 675mg.
Wherein, the preparation method of compound 10-1 is referring to Bulletin of the Chemical Society of Japan, 2009 (82), 555-562.
Step 14. is synthesized (1S, 2S, 3S, 4R, 5S)-1-(acetoxy-methyl)-5-(the chloro-3-of 4-((5-(4-aminomethyl phenyl) thiophene-2-yl) methyl) phenyl)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-, tri-base triacetates (formula 10-3)
Figure BDA00002313195600293
Operation is with the step 18 in embodiment 1, and difference is that the consumption of compound 10-2 is 363mg(0.785mmol), the consumption of compound m is 443mg(0.785mmol), obtain product white solid (262mg, 51%).LC-MS:679.1[M+Na] +。
Step 15. is synthesized (1S, 2S, 3S, 4R, 5S)-5-(the chloro-3-of 4-((5-(4-aminomethyl phenyl) thiophene-2-yl) methyl) phenyl)-1-(methylol)-6,8-dioxa two encircles [3.2.1] octane-2,3,4-triol (compound 10)
Figure BDA00002313195600301
Operation is with the step 19 in embodiment 1, and difference is that the consumption of compound 10-3 is 66mg(0.10mmol), obtain final product white solid (31mg, 63%).LC-MS:511.1[M+Na] +。
1H NMR(400MHz,CD 3OD):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)。
Embodiment 11 above-claimed cpd of the present invention suppresses active and selects ratio for SGLT-2, SGLT-1
Healthy human body exceedes 99% blood sugar and reuptakes blood back liquid after by glomerular filtration, is excreted in urine less than 1% blood sugar, and this process completes by sodium dependent glucose transporter (SGLT1/2).The SGLT1 of high-affinity, low turn-over capacity is mainly distributed in stomach, heart and kidney (completing 10% glucose in urine heavily absorbs), heavily absorbs and the SGLT2(of low-affinity, high turn-over capacity completes 90% glucose in urine), be mainly distributed in kidney.Suppressing SGLT1 can cause as serious negative consequences such as hereditary syndrome glucose/semi-lactosi malabsorptions (GGM), not only can improve hypoglycemic effect in chemical combination object so improve compound for the selection ratio of SGLT1/SGLT2, and significant for drug safety.
Experimental technique please refer to document: J.Med.Chem.2008,51,1145-1149..
Inoculation is expressed the CHOK1 cell of mankind SGLT-2 or SGLT-1 to 24-hole analysis plates, this analysis plates is containing the F-12 nutrient substance compound of 10% foetal calf serum, 400 μ g/mL Geneticins, 50 units/mL benzylpenicillin sodium G and 50 μ g/mL streptomycin sulfates, and density is 400000 cells/well.Cultivate after 2 days in the damp atmosphere of the CO2 containing 5% in 37 ℃, with analysis buffer (137mMNaCl, 5mM KCl, the 1mM CaCl of pH 7.4 2, 1mM MgCl 2, 50mM 4-hydroxyethyl piperazine ethanesulfonic acid and 20mM Tutofusin tris) washed cell once, then with 250 μ L the damping fluid containing experimental compound (being SGLT-2 inhibitor prepared by the various embodiments described above), at 37 ℃, cultivate 10 minutes.Experimental compound is dissolved in DMSO.The ultimate density of DMSO is 0.5%.By adding 50 μ L[14C]-methyl-α-D-glucopyranoside (14C-AMG) solution starts transhipment reaction.At 37 ℃, cultivate after 2 hours, separate out culturing mixt, with cold PBS(phosphate buffered saline buffer) cell washing 3 times.Then with 0.3N NaOH dissolved cell, and get equal portions cell and utilize liquid flashing counter measuring radioactivity.Non-specific AMG absorptivity is defined as the absorptivity under 100 μ M phlorizins (for sodium dependent glucose translocator specific inhibitor) exist.Proofread and correct specificity absorptivity by the protein concn that Bradford method is measured.50% inhibition concentration (IC 50) value utilizes least square method to calculate by dose response curve.
Experimental result: the biological activity test of representative compound of the present invention the results are shown in Table 2,3.
Table 2: compound of the present invention suppresses active to SGLT-2
The compounds of this invention is external as can be seen from Table 2 has stronger inhibition activity for SGLT-2, is all better than marketed drug Dapagliflozin (BMS contrasts medicine), shows that the compounds of this invention has excellent activity.Especially compound 1, its external activity is greatly due to Dapagliflozin.
Table 3: compound of the present invention is selected than (SGLT1 activity/SGLT2 activity)
The compounds of this invention SGLT1/SGLT2 selects than being better than marketed drug Dapagliflozin (BMS contrasts medicine) and Pfizer's contrast medicine as can be seen from Table 3, especially compound 3, in the situation that keeping better activity (active suitable with Dapagliflozin), select to contrast medicine than being greatly better than Pfizer.And compound 1, in the situation that keeping suitable with Pfizer's contrast medicine activity, is selected than being also better than Pfizer's contrast medicine.Can cause as serious negative consequences such as hereditary syndrome glucose/semi-lactosi malabsorptions (GGM) owing to suppressing SGLT-1, therefore, improve the selection ratio of compound for SGLT1/SGLT2, significant for hypoglycemic effect and drug safety in raising chemical combination object.
Embodiment 12 compound 8 normal rat internal metabolism experiments
Experimental technique:
4 of healthy SD rats, male, body weight 200-220g, gavage gives compound 8, and dosage is 20mg/kg, and administration volume is 10ml/kg; Fasting 12h before test, freely drinks water.The unified feed of 2h after administration.Medicine is mixed with suspension with 0.5%CMC-Na.After administration 0.25,0.5,1.0,2.0,3.0,4.0,5.0,7.0,9.0 and 24h through rat eye rear vein beard extracting vein blood 0.3ml, put in heparinization test tube, the centrifugal 10min of 3000rpm, 20 ° of C refrigerator and cooled of separated plasma ， Yu – are frozen.Use LC/MS method to measure the plasma concentration of each sampling spot.Experimental result is as shown in table 4 below.
Table 4: compound 8 is for normal rat internal metabolism data sheet
The compounds of this invention 8 has good Pharmacokinetics in Rat parameter as can be seen from Table 4: longer Half-life in vivo (8.86h) and desirable drug disposition exposed amount (46043ng*h/mL).Show that the compounds of this invention has obvious quasi-medicated property, be applicable to the disease that treatment or prevention are relevant to SGLT-2, as diabetes, obesity etc.
Embodiment 13 rat urine glucose Emission tests
Measuring rat urine glucose quantity discharged and concentration, is an important indicator of check SGLT2 inhibitor hypoglycemic validity.
Get 30 of the qualified healthy male rats (body weight 180～220g) of quarantine, be divided at random 5 groups, every group 6, be respectively solvent control group, compound group, respectively organize after rat fasting 12h, gastric infusion respectively, dosage is 10mg/kg, and administration volume is 1.0mL/100g, after administration, rat is put into metabolic cage, measure urine amount and urine sugar value in 24h, measurement result is as shown in table 5.
The impact of table 5 representative compound of the present invention on normal rat urine glucose discharge
Compound Urine amount (mL) Glucose in urine concentration (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**
*: with the comparison of solvent control group, there is significant difference (p<0.01)
As can be seen from Table 5: with the comparison of solvent control group, the compounds of this invention has significantly short glucose discharge effect for the urine of normal rat, especially compound 8 is respectively 4126.0 ± 835.1 μ g/dL and 1373.9 ± 128.1mg for urinate concentration and glucose in urine total amount of Rat 24 h, respectively compared with solvent control group height 37 times and 78 times.Further show that the compounds of this invention has hypoglycemic activity in obvious body.
Sum up: can find out from table 2,3,4,5, the inventor has completed the external activity experiment to a series of compounds, external selection is than measuring, and internal metabolism is tested and glucose in urine experiment.Good experimental result can be found out, we have found a series ofly has very strong inhibition activity to SGLT-2, simultaneously higher than also to the selection of SGLT-1 and SGLT-2, can be used for preparing the compound for the treatment of and prevention and sodium dependent glucose translocator relative disease.

Claims (10)

1. compound or its optical isomer shown in a general formula (I):
Figure FDA00002313195500011
Wherein:
R 2be selected from: hydrogen, chlorine or methyl;
Y is selected from: C=C or S;
R 1be selected from:
Figure FDA00002313195500012
Figure FDA00002313195500013
Wherein, R 3be selected from: hydrogen, fluorine, chlorine, bromine, methyl or trifluoromethyl.
2. compound according to claim 1, is characterized in that, described R 2for chlorine.
3. compound according to claim 2, is characterized in that, described Y is C=C, described R 1be selected from:
Figure FDA00002313195500014
4. compound according to claim 3, is characterized in that, described compound is:
Figure FDA00002313195500015
5. compound according to claim 2, is characterized in that, described Y is S, described R 1for 4-fluorophenyl, 4-trifluoromethyl or 4-aminomethyl phenyl.
6. the purposes of arbitrary formula (I) compound in claim 1-5, is characterized in that, for the preparation of the medicine for the treatment of or the prevention disease relevant to sodium dependent glucose transport protein 2.
7. purposes according to claim 6, is characterized in that, the described disease relevant to sodium dependent glucose transport protein 2 comprises complication and the obesity of diabetes, diabetes.
8. the preparation method of arbitrary formula (I) compound in claim 1-5, is characterized in that, comprises the following steps:
1), at 20～160 ℃, in polar aprotic solvent, under alkali and palladium catalyst effect, formula iii compound and formula ii tin reagent generation linked reaction, obtain formula iv compound:
Figure FDA00002313195500021
2) at 0～100 ℃, in polar protic solvent, under the effect of alkali, formula iv compound removes acetate, obtains formula (I) compound:
Figure FDA00002313195500022
Wherein, R 1, R 2, Y as above defines.
9. method according to claim 8, is characterized in that, the reaction conditions of step 1) is as follows: solvent is Isosorbide-5-Nitrae-dioxane, and alkali is salt of wormwood, and palladium catalyst is Pd (PPh 3) 4, temperature of reaction is 80-140 ℃, the reaction times is 5-15 hour.
10. method according to claim 8, is characterized in that step 2) reaction conditions as follows: solvent is methyl alcohol, and alkali is sodium methylate, and pH value of solution is 11, and temperature of reaction is room temperature, and the reaction times is 0.1-5 hour.
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