CN101279993A - 3-aryl-8-hydroxychromone-7-O-alpha-D-arabinofuranoside compound, synthetic method and use thereof - Google Patents
3-aryl-8-hydroxychromone-7-O-alpha-D-arabinofuranoside compound, synthetic method and use thereof Download PDFInfo
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Abstract
The invention provides 3-aryl-8-hydroxyl-chromone-7-O-Alpha-D-furan arabinoside compound(A-76202analog)with strong inhibiting activity to Alpha-glucosaccharaseI, II, the synthesis method and application thereof. The method includes the following steps: (1)synthesizing 7,8-dihydroxy chromone;(2)selectively disrobing 7-hydroxyl;(3) synthesizing 8-hydroxyl-7-(2,3,5-tri-O-acetyl-Alpha furan arabinoside) chromone; (4) brominating glycoside-3- of chromone; (5) desorbing the protecting group of acyl; (6) constructing isoflavone B Ring through Suzuki coupled reaction. The A-76202 analog prepared with the method is of strong inhibiting activity to Alpha-glucosaccharaseI, II and is of promising prospect in the development of the drugs for diabetesm, obesity, glycosphingolipid lysosome storage diseases,HIV infection and tumour.
Description
Technical field
The present invention relates to the A-76202 analogue, especially 3-aryl-8-hydroxyl chromone-7-O-α-D-arabinofuranoside compound and preparation method and use thereof.
Background technology
A-76202 is that Japanese scientist separates isoflavone aglycone compound [Takatsuki, an Akira who obtains from Rhodococcus sp.SANK61694; Nakajima, Mutsuo; Ando, Osamu; Takamatsu, Yasuyuki; Kinoshita, Takeshi; Haruyama, Hideyuki; Okazaki, Hisao; Enokida, Ryuzo (Sankyo Co, Japan) .Jpn.Kokai Tokkyo Koho JP 08134091 A2 28 May 1996 Heisei, 12pp. (Japan) .], this compound has intensive inhibition activity, IC to alpha-glucosidase I and II
50Be 0.46ng/ml.Shiozaki in 1999 have finished its complete synthesis first work [Shiozaki, M.Synthesis of 4 ', 8-dihydroxyisoflavon-7-yl-D-arabinofuranoside.Tetrahedron.:Asymmetry 1999,10,1477-1482.], we have finished its synthetic [Li, M. once more by improved method in 2003; Han, X.; Yu, B.Facile Synthesis of Flavonoid 7-O-Glycosides.J.Org.Chem.2003,68,6842-6845.].
Compd A-76202 structure
Calendar year 2001, Shiozaki has synthesized four six carbon pyranosides [Watanabe, the Y. of A-76202; Shiozaki, M.; Kamegai, R.Synthesis and biological activity of4 ', 8-dihydroxyisoflavon-7-yl D-hexopyranosides.Carbohydr.Res.2001,335,283-289.], and tested its alpha-glucosidase and suppressed active, four A-76202 analogues of institute's synthetic activity all has remarkable reduction.
Four six carbon pyranosides of Shiozaki synthetic
The relevant preparation and the patent of active aspect also have: (1) Takatsuki, Akira; Nakajima, Mutsuo; Ando, Osamu; Takamatsu, Yasuyuki; Kinoshita, Takeshi; Haruyama, Hideyuki; Okazaki, Hisao; Enokida, Ryuzo (Sankyo Co, Japan) .Jpn.Kokai Tokkyo Koho JP09003090 A2 7 Jan 1997 Heisei, 11 pp. (Japan). (2) Shiozaki, Masao (Sankyo Co., Ltd., Japan) .Jpn.Kokai Tokkyo Koho JP 2000186098 A2 4 Jul 2000,10 pp. (Japan). (3) Kazama, Yukiko; Shiosaki, Tadao (Sankyo Co., Ltd., Japan) .Jpn.KokaiTokkyo Koho JP 2001089495 A2 3 Apr, 2001,15 pp. (Japan).
Summary of the invention
The problem to be solved in the present invention provides the new A-76202 compound of a class, especially 3-aryl-8-hydroxyl chromone-7-O-α-D-arabinofuranoside compound;
The problem that the present invention also will solve is the synthetic method of the practicality of 3-aryl-8-hydroxyl chromone-7-O-α-D-arabinofuranoside compound;
The problem that the present invention also will solve is the purposes of 3-aryl-8-hydroxyl chromone-7-O-α-D-arabinofuranoside compound.
The present invention is to provide and have alpha-glucosidase and suppress active 3-aryl-8-hydroxyl chromone-7-O-α-D-arabinofuranoside compound general formula and be:
Ar contains different fragrance or the condensed ring aromatic substituents that replace, and specifically can be
With
Deng aromatic substituent, wherein X can be CH or N, and it is H, OR that R can be H, R
1, SR
1, NR
1R
2Or YR
1R
2R
3(wherein Y is C, N, O, S, Si etc., R
1, R
2And R
3Identical or different, can be respectively H, Boc, C
1-C
6Alkyl, halogen or C
1-C
6Haloalkyl), ZCOOR
4(wherein Z is CH
2, NH, O or S, R
4Be H or C
1-C
6Alkyl substituent) or halogenic substituent (F, Cl, Br, I), the position of R can be that ring goes up can substituted optional position, R is single replacement or the multi-substituent on aromatic ring or the heterocycle.Wherein Boc represents tertbutyloxycarbonyl.
Recommending described X is CH, and R is H, C
1-C
6Alkoxyl group, C
1-C
6Alkyl, C
1-C
6The amido that replaces of alkyl.
The synthetic method of the practicality of 3-aryl provided by the present invention-8-hydroxyl chromone-7-O-α-D-arabinofuranoside compound has following steps (6), (5)～(6), (4)～(6), (3)～(6), (2)～(6) or (1)～(6):
Synthesizing of (1) 7,8-dihydroxyl chromone: petroleum benzene triphenol and acetic acid are at BF
3OEt
2Catalysis heating (recommending 80～110 ℃) down obtains the phenyl ring acetylate, again at HC (OEt)
2/ HCl0
4(recommend HC (OEt) under the condition
2/ 70%HClO
4) the heating ring symphysis becomes the chromogen ketone compound.It is 0.8～1.5 equivalent that the mole dosage of acetic acid is recommended, and further is recommended as 1.1 equivalents; HC (OEt)
2Recommending mole dosage is 5 equivalents, and perchloric acid is recommended to be about 1: 10 in the molar ratio of triethyl orthoformate.
(2) selectivity of chromone 7-hydroxyl is exposed: behind two phenolic hydroxyl groups of caproyl protection chromone, utilize PhSH/ imidazoles condition that the transesterification selectivity takes place in nmp solvent and expose 7-OH and be used for glycosylation reaction.Imidazoles is recommended in-10～10 ℃ of especially ice-water bath cooling slowly droppings down, and the imidazoles mole dosage is recommended as 0.2～0.5 equivalent of chromone, especially recommends to be about 0.4 equivalent, and reaction is recommended in the ice-water bath to be carried out.Reaction times recommended 2～4 hours.
(3) 8-hydroxyl-7-O-(2,3,5-three-O-ethanoyl-α-D-arabinofuranosyl) chromone is synthetic: with BF
3OEt
2Do promotor, in organic solvent such as methylene dichloride, the chromone that the selectivity that step (2) obtains exposes 7-OH obtains 7-glycosylation reaction product in 0 ℃～room temperature and D-pectinose to precursor reactant.The glycosyl donor consumption is recommended as 1～2 equivalent, is recommended as 1.5 equivalents, and catalyzer mole dosage illustrated handbook is 0.05～0.2 equivalent, further is recommended as 0.1 equivalent, and catalyzer is recommended in the ice-water bath cooling and drips down, rises to room temperature naturally, and the reaction times recommended 2～3 hours.
(4) bromo of chromogen ketoside-3-position: with the bioactive molecule bromine chromogen ketoside is carried out bromination 0 ℃～room temperature and obtain chromone glucosides bromide.Recommendation is with PhI (OAc)
2/ TMSBr carries out bromination reaction at the bioactive molecule bromine of 0 ℃ of generation to substrate.For example earlier with PhI (OAc)
2Be dissolved in a spot of methylene dichloride, 0 ℃ drips TMSBr (about 2 equivalents) down, stirs the dichloromethane solution and the pyridine (about 4 equivalents) that drip the chromone glucosides after 30 minutes, and the reaction times recommended about 8～10 hours.Wherein TMSBr represents bromotrimethylsilane, and Ac is an ethanoyl.
(5) removing of acyl group protecting group: recommend with K
2CO
3Make alkali, at aqueous organic solvent such as MeOH-THF-H
2Reaction obtains the naked dew product of hydroxyl in O (2: 1: the 0.2) solvent.K
2CO
3Consumption is recommended as 4 equivalents, and the stirring at room time recommended 2～3 hours.
(6) the Suzuki linked reaction makes up chromone 3-position and is connected with C-C key between aryl: with Pd (OAc)
2(recommend 0.05～0.1 equivalent) be catalyzer, and SPhos (be recommended as catalyzer three times) is for part or do not add part, and recommendation is with 0.4M K
2CO
3Or Na
2CO
3(3 equivalent) makes alkali, and look unit ketone bromide and corresponding boronic acid compounds recommend 30～65 ℃ to heat 2-10 hour in nonelectrolyte mixed aqueous solution (being recommended as acetone-water 1: 1) solvent, further recommend 50 ℃ to heat 2-5 hour, recommendation TLC monitoring reaction progress.Wherein SPhos is the efficient Suzuki-Miyaura coupling part of people such as Buchwald in development in 2004, reference Walker, S.D.; Barder, T.E.; Martinelli, J.R.; Buchwald, S.L.A rationally designed universal catalyst for Suzuki-Miyaura coupling processes.Angew.Chem.Int.Ed.2004,43, (14), 1871-1876
3-aryl of the present invention-8-hydroxyl chromone-7-O-α-D-arabinofuranoside compound can be used for preparing medicine, in particular for the medicine of preparation inhibition alpha-glucosidase activity, for example preparation treatment diabetes, obesity, glycosphingolipid LSD, HIV infect and the medicine of tumour.
Embodiment:
Embodiment 1
8-hydroxyl-3 '-methoxyl group isoflavones-7-O-α-D-furans Arabinoside (8d)
Synthetic route is as follows:
Reagent and condition: a) AcOH, BF
3OEt
2, 90～100 ℃, 4h, 96%; B) HC (OEt)
3, 70%HClO
4, 85 ℃, 12h, 82%; C) i, CH
3(CH
2)
4COCl, Pyridine, 0 ℃-rt, 16h; Ii, PhSH, Imidazole, NMP, 0 ℃-rt, 3h, 70%; D) BF
3OEt
2, CH
2Cl
2, 4
MS, rt, 62%; E) PhI (OAc)
2/ TMSBr, CH
2Cl
2, Pyridine, 0 ℃-rt, 68%; F) K
2CO
3, MeOH-THF-H
2O (2: 1: 0.2), rt, 77%; G) Pd (OAc)
2, SPhos, K
2CO
3, Acetone-H
2O, 50 ℃, 4h, 75%.
Concrete experiment and data:
(1)1-(2，3，4-Trihydroxyphenyl)ethanone(2)
Under the argon shield, with petroleum benzene triphenol 1 (12.61g, 100mmol) and AcOH (64ml, 110.9mmol 1.1eq.) are dissolved in the boron trifluoride diethyl etherate (37ml) of new steaming, 90 ℃ of-100 ℃ of following heated and stirred backflow 4h, stopped reaction.After reaction solution was cooled to room temperature, among the NaOAc of impouring 600ml 10%, stirring was spent the night.After extracted with diethyl ether, organic phase are concentrated into original volume 1/3,, use anhydrous Na then with saturated NaCl washing
2SO
4Drying is filtered, filtrate decompression concentrate light yellow solid 2 (16.1g, 96%).R
f?0.69(DCM∶MeOH＝10∶1)。Crude product is purifying not, directly drops into the next step.
(2)7，8-Dihydroxy-4H-chromen-4-one(3)
Under the argon shield, with 2 (10.0g, 59.47mmol) be suspended in triethyl orthoformate (50ml, 300mmol, 5.0eq.) in, slowly drip 70%HClO
4, reaction color deepens gradually, drips to finish, and reaction is moved in the oil bath pan 85 ℃ of reflux 12h, stopped reaction.After reaction solution was cooled to room temperature, to wherein adding the 200ml anhydrous diethyl ether, agitation and filtration went out throw out, added 100ml water in throw out, and stirring is spent the night, and filters, and filtration cakes torrefaction gets khaki color solid 3 (8.72g, 82%).R
f?0.45(CH
2Cl
2∶MeOH＝10∶1)。
(3)7-Hydroxy-4-oxo-4H-chromen-8-yl?hexanoate(4)
Under the argon shield, (6.8g 38.17mmol) is dissolved in the pyridine (60ml), and the ice-water bath cooling drips caproyl chloride down, and (27ml 195.6mmol), drips and finishes, and continues to stir in ice-water bath, rises to room temperature naturally, stopped reaction behind the 16h with 3.In reaction solution, add the methylene dichloride dilution, successively with 1N aq.HCl and saturated NaCl washing, anhydrous Na
2SO
4Drying is filtered, and filtrate decompression concentrates, and directly carries out next step reaction.
Under the argon shield, (1.10g 15.84mmol) is dissolved among the anhydrous NMP (60ml) fully with thick product and imidazoles.Ice-water bath is cooled to 0 ℃, drips PhSH, finishes, and continues to stir in ice-water bath, rises to room temperature naturally, stopped reaction behind the 3h.In reaction solution, add trichloromethane (300ml) dilution, with 1N aq.HCl and saturated NaCl washing, use anhydrous Na then successively
2SO
4Drying is filtered, and filtrate concentrates after silica gel column chromatography (PE: EtOAc=2: 1) get light yellow solid 4 (7.64g, 70%for two steps).R
f?0.17(PE∶EtOAc＝2∶1)。
1H?NMR(300MHz，CDCl
3)δ8.28(br?s，1H)，7.98(d，1H，J＝9.0Hz)，7.79(d，1H，J＝5.7Hz)，7.11(d，1H，J＝9.0Hz)，6.32(d，1H，J＝5.7Hz)，2.71(t，2H，J＝7.5Hz)，1.82(quintet，2H，J＝7.2Hz)，1.48-1.35(m，4H)，0.93(t，3H，J＝6.9Hz).ESI-MS(m/z)：277.1[M+H+].
(4)8-(Hexanoyloxy)-4-oxo-4H-chromen-7-yl?2，3，5-tri-O-acetyl-α-D-arabinofuranoside(5)
Under the argon shield, with 4 (7.64g, 27.65mmol) and the D-pectinose give body (17.86g; 42.46mmol, 1.54eq.) be dissolved in the anhydrous methylene chloride (200ml), add the new molecular sieve that burns; stir 15min; dropping boron trifluoride diethyl etherate under the ice-water bath cooling (2.8ml, 2.80mmol, 0.1eq.); drip and finish; continuation is stirred in ice-water bath, rises to room temperature naturally, stopped reaction behind the 3h.In reaction solution, add triethylamine (5ml) cancellation reaction, concentrate after silica gel column chromatography (PE: EtOAc=2: 1) get syrup thing 5 (9.1g, 62%).R
f0.53(PE∶EtOAc＝1∶1)。
1H NMR (300MHz, CDCl
3) δ 8.05 (d, 1H, J=9.0Hz), 7.78 (d, 1H, J=6.3Hz), 7.31 (d, 1H, J=9.0Hz), 6.30 (d, 1H, J=6.3Hz), 5.79 (s, 1H), 5.38 (s, 1H), 5.11 (br s, 1H), 4.50-4.20 (m, 3H), 2.68 (t, 2H, J=7.8Hz), 2.16 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H), 1.84 (quintet, 2H, J=7.5Hz), 1.51-1.30 (m, 4H), 0.96 (t, 3H, J=6.6Hz);
13C NMR (75MHz, CDCl
3) δ 176.4,170.5,170.4,169.9,169.4,154.8,152.0,149.9,128.8,123.6,120.7,113.8,113.0,104.5,82.0,81.1,76.7,62.7,33.7,31.2,24.6,22.2,20.7,20.6,13.9; ESI-MS (m/z): 535.3 (M+H
+), 557.3 (M+Na
+); HRMS (MALDI) calculated value (calcd for) C
26H
30O
12Na
+557.1630, theoretical value (Found) 557.1638.
(5)3-Bromo-8-(hexanoyloxy)-4-oxo-4H-chromen-7-yl?2，3，5-tri-O-
acetyl-α-D-arabinofuranoside(6)
PhI (OAc)
2(10.6g, 32.71mmol 3.0eq.) are dissolved among the anhydrous DCM of 50ml, and the ice-water bath cooling drips TMSBr down, and (8.6ml, 64.96mmol 6.0eq.), dropwise continuation and stir 45min in ice-water bath.Drip DCM (25ml) solution of chromone glycoside compound 5, rise to stirring at room 2h naturally; (5.7ml, 66.47mmol 6.13eq.), have a large amount of smog to produce, and continue stirring reaction 1h, and TLC shows that raw material 5 disappears to add anhydrous pyridine.Reaction solution dilutes with DCM, and organic phase is used saturated Na successively
2S
2O
3, saturated NaCl washing, anhydrous Na
2SO
4Dry.Filter, filtrate concentrates after silica gel column chromatography (PE: EtOAc=3: 1,5: 2) purifying, pale brown sugar colour slurry 6 (4.5g, 67%).R
f0.85(PE∶EtOAc＝1∶1)。
1H?NMR(300MHz，CDCl
3)δ8.15(s，1H)，8.11(d，1H，J＝9.0Hz)，7.35(d，1H，J＝9.0Hz)，5.80(s，1H)，5.38(s，1H)，5.12(d，1H，J＝3.6Hz)，4.46-4.25(m，3H)，2.68(t，2H，J＝7.5Hz)，2.16(s，3H)，2.14(s，3H)，2.11(s，3H)，1.83(quintet，2H，J＝7.2Hz)，1.48-1.35(m，4H)，0.96(t，3H，J＝6.6Hz)；
13C?NMR(75MHz，CDCl
3)δ171.2，170.4，170.38，169.9，169.4，153.2，152.3，149.6，128.6，124.2，118.8，114.5，110.9，104.5，82.2，81.1，76.7，62.7，33.7，31.2，24.6，22.2，20.7，20.62，20.60，13.9；ESI-MS(m/z)：613.1(M+H
+)，635.2(M+Na
+)；HRMS(MALDI)calcd?for?C
26H
29O
12BrNa
+635.0735，Found：635.0721.
(6)3-Bromo-8-hydroxy-4-oxo-4H-chromen-7-yl?α-D-arabino-furanoside(7)
(585mg 0.954mmol) is dissolved in MeOH-THF-H with the chromone glucosides 6 of acidylate
2O (2: 1: 0.2,50ml) in the mixed system, add anhydrous K
2CO
3(527mg, 3.82mmol, 4.0eq.), the stirring at room reaction.The TLC demonstration reacts completely behind the 10h, and acidic resins are transferred pH value of solution 7, stir 15min, filter, and filtrate decompression concentrates, and (DCM: MeOH=8: 1) purifying gets yellow solid 7 (287mg, 77%) to resistates through silica gel column chromatography.R
f0.41(DCM∶MeOH＝10∶1)；[α]
D 24＝74.7(c0.20，MeOH)；
1H?NMR(300MHz，CD
3OD)δ8.57(s，1H)，7.56(d，1H，J＝9.0Hz)，7.33(d，1H，J＝9.0Hz)，5.72(s，1H)，4.36(d，1H，J＝2.1Hz)，4.13(dd，1H，J＝9.0Hz，4.5Hz)，4.05-4.03(m，1H)，3.77-3.60(m，2H)；ESI-MS(m/z)：410.8(M+Na
+)，412.7(M+2+Na
+).
(7)8-Hydroxy-3′-methoxyisoflavon-7-yl α-D-arabinofuranoside(8d)
(50mg, 0.129mmol) (29mg, 0.195mmol 1.5eq.) are dissolved in Acetone-H with the 3-methoxyphenylboronic acid with 3-bromine chromogen ketoside 7
2O (1: 1,1.0ml) in, add Pd (OAc) under the argon shield successively
2(1.5mg, 0.0067mmol, 0.05eq.), part SPhos (8.0mg, 0.0195mmol, 0.15eq.) and anhydrous K
2CO
3(54mg, 0.390mmol, 3.0eq.), and 50 ℃ of stirring reaction 4h of oil bath, the TLC detection reaction is complete.Reaction solution is directly helped filter through silica gel (300-400 order), and filtrate concentrates after preparation thin-layer chromatography (DCM: MeOH=8: 1) separate, get target product 8d (40mg, 74.5%).R
f0.29(CHCl
3∶MeOH＝10∶1)；[α]
D 24＝27.6(c?0.13，MeOH)；
1H?NMR(300MHz，CD
3OD)δ8.36(s，1H)，7.57(d，1H，J＝9.0Hz)，7.43-7.31(m，2H)，7.24-7.09(m，2H)，6.99(d，1H，J＝9.0Hz)，5.76(br?s，1H)，4.40(br?s，1H)，4.22-4.15(m，1H)，4.07-4.03(m，1H)，3.85(br?s，3H)，3.80-3.60(m，2H)；
13C?NMR(75MHz，CD
3OD)δ179.1，161.4，156.1，150.5，145.9，144.5，135.2，130.7，125.6，122.8，121.7，116.4，116.2，115.0，113.8，109.1，88.5，83.0，78.9，63.3，56.1；ESI-MS(m/z)：417.2(M+H
+)，439.2(M+Na
+)，455.2(M+K
+)；HRMS(MALDI)calcd?for?C
21H
21O
9 +417.1180，Found：417.1188.
Embodiment 2
4 '-fluoro-8-hydroxy-isoflavone-7-O-α-D-furans Arabinoside (8j)
Reaction process:
Experimental implementation and data:
(50mg, 0.129mmol) (27mg, 0.195mmol 1.5eq.) are dissolved in Acetone-H with the 4-fluorobenzoic boric acid with 3-bromine chromogen ketoside 7
2O (1: 1,1.0ml) in, add Pd (OAc) under the argon shield successively
2(1.5mg, 0.0067mmol, 0.05eq.), part SPhos (8.0mg, 0.0195mmol, 0.15eq.) and anhydrous K
2CO
3(54mg, 0.390mmol, 3.0eq.), 50 ℃ of stirring reactions of oil bath, TLC monitoring reaction progress.After chromogen ketoside raw material reaction was complete, reaction solution directly helped filter through silica gel (300-400 order), and filtrate concentrates after preparation thin-layer chromatography (DCM: MeOH=8: 1) separate, get target product 8j (16mg, 31%).R
f0.42(CHCl
3∶MeOH＝8∶1)；[α]
D 24＝31.6(c0.16，MeOH)；
1HNMR(300MHz，CD
3OD)：δ＝8.34(s，1H)，7.65-7.56(m，3H)，7.34(d，J＝9.0Hz，1H)，7.19(t，J＝8.4Hz，2H)，5.77(s，1H)，4.41(br?s，1H)，4.21(dd，J＝8.7Hz，4.5Hz，1H)，4.09(m，1H)，3.78(dd，J＝11.7Hz，3.9Hz，1H)，3.73(dd，J＝11.7Hz，5.1Hz，1H)；ESI-MS(m/z)：405.2(M+H
+)，427.2(M+Na
+)；HRMS(ESI)calcd?forC
20H
17O
8FNa
+?427.0800，Found：427.0795.
Embodiment 3
4 '-dimethylamino-8-hydroxy-isoflavone-7-O-α-D-furans Arabinoside (8k)
Reaction process:
Concrete operations and data:
(50mg, 0.129mmol) (32mg, 0.195mmol 1.5eq.) are dissolved in Acetone-H with 4-dimethylamino phenylo boric acid with 3-bromine chromogen ketoside 7
2O (1: 1,1.0ml) in, add Pd (OAc) under the argon shield successively
2(1.5mg, 0.0067mmol, 0.05eq.), part SPhos (8.0mg, 0.0195mmol, 0.15eq.) and anhydrous K
2CO
3(54mg, 0.390mmol, 3.0eq.), and 50 ℃ of stirring reaction 3h of oil bath, the TLC monitoring reaction is complete.Reaction solution is directly helped filter through silica gel (300-400 order), and filtrate concentrates after preparation thin-layer chromatography (DCM: MeOH=8: 1) separate, get target product 8j (20mg, 36%).R
f0.30(CHCl
3∶MeOH＝10∶1)；[α]
D 24＝104.6(c?0.10，MeOH)；
1H?NMR(300MHz，CD
3OD)：δ＝8.22(s，1H)，7.43(d，J＝8.4Hz，3H)，7.25(d，J＝9.0Hz，1H)，6.84(d，J＝8.4Hz，2H)，5.69(s，1H)，4.40(br?s，1H)，4.20(dd，J＝8.7Hz，4.5Hz，1H)，4.02(m，1H)，3.77(dd，J＝11.7Hz，3.0Hz，1H)，3.71(dd，J＝11.7Hz，5.1Hz，1H)，2.96(br?s，6H)；
13C?NMR(75MHz，CD
3OD)：δ＝180.0，155.0，152.3，150.6，144.4，131.1，125.6，122.1，116.7，124.0，112.1，109.1，88.3，83.0，79.0，63.4，41.1；ESI-MS(m/z)：430.0(M+H
+)；HRMS(ESI)calcd?for?C
22H
23O
8NNa
+?452.1316，Found：452.1320.
Embodiment 4
8-hydroxyl-3 '-methyl isoflavones-7-O-α-D-furans Arabinoside (8g)
Reaction process:
Concrete operations and data:
(50mg, 0.129mmol) (26mg, 0.195mmol 1.5eq.) are dissolved in Acetone-H with the 3-methylphenylboronic acid with 3-bromine chromogen ketoside 7
2O (1: 1,1.0ml) in, add Pd (OAc) under the argon shield successively
2(1.5mg, 0.0067mmol, 0.05eq.), part SPhos (8.0mg, 0.0195mmol, 0.15eq.) and anhydrous K
2CO
3(54mg, 0.390mmol, 3.0eq.), and 50 ℃ of stirring reaction 3h of oil bath, the TLC monitoring reaction is complete.Reaction solution is directly helped filter through silica gel (300-400 order), and filtrate concentrates after preparation thin-layer chromatography (DCM: MeOH=8: 1) separate, get target product 8g (27mg, 52%).R
f0.35(CHCl
3∶MeOH＝10∶1)；[α]
D 24＝17.7(c0.13，MeOH)；
1H?NMR(300MHz，CD
3OD)：δ＝8.32(s，1H)，7.78-7.63(m，2H)，7.42-7.29(m，3H)，7.22(br?s，1H)，5.79(s，1H)，4.43(br?s，1H)，4.21(dd，J＝8.7Hz，4.5Hz，1H)，4.10(m，1H)，3.78(dd，J＝11.7Hz，3.9Hz，1H)，3.71(dd，J＝11.7Hz，5.1Hz，1H)，2.41(s，3H)；ESI-MS(m/z)：401.2(M+H
+)，423.2(M+Na
+)，439.2(M+K
+)；HRMS(ESI)calcd?forC
21H
20O
8Na
+?423.1050，Found：423.1051.
Alpha-glucosidase suppresses activity research
Adopt the rat liver microsomes enzyme system to carry out active testing as alpha-glucosidase:
1) preparation of enzyme: the secondary centrifuging legal system according to bibliographical information is equipped with the hepatomicrosome enzyme system.After 10 160～200g male Sprague-Dawley rat sacrificed by decapitation, get its hepatic tissue rapidly, with 0.15mol/L KCl-0.1mol/L phosphate buffered saline buffer flush away oxyphorase, then hepatic tissue is shredded, under cooled with liquid nitrogen, smash into homogenate.After adding the dilution of 100ml phosphate buffered saline buffer, supernatant liquor with the centrifugal 20min of 9000 * g, is got by elder generation under 4 ℃, place on the ultracentrifuge in 100000 * g (32000r/min) 4 ℃ of centrifugal 1h down, abandoning supernatant again, get the pink precipitation and be dissolved in 25%Triton X-100, diluted for use.
2) damping fluid: 0.15mol/L KCl-0.1mol/L phosphate buffered saline buffer, pH 6.8.
3) substrate: 4-Nitrophenol α-D-glucopyranoside.
4) testing method: testing compound sample solution (in DMSO) the 5 μ L and the enzyme solution 20 μ L of different concns are added on the 96 hole enzyme plates, and dilute with 105 μ L damping fluids, incubate 5min in advance in 37 ℃, add substrate solution 20 μ L (20mM) then, immediately on microplate reader the METHOD FOR CONTINUOUS DETERMINATION reaction soln at the absorbancy 30min of 400nm, calculate substrate hydrolysis speed, and then estimate the alpha-glycosidase inhibiting rate of each compound.Each compound is got five different concns and (is comprised IC
50), its mean value calculation is got in each concentration repeated test three times.IC
50Be to try to achieve by inhibiting rate-compound concentration curve.
By aforesaid method, we are to 3-aryl that part is synthesized-ketone-result is as follows for 7-O-α-D-arabinofuranoside compound active testing in 8-hydroxyl look unit:
Claims (10)
1. 3-aryl-8-hydroxyl chromone-7-O-α-D-arabinofuranoside compound is characterized in that having following structural formula:
Described Ar is hexa-atomic aromatic ring or fragrant heterocyclic substituent
Or
Wherein X can be CH or N, and go up for ring the position of R can substituted optional position, and R is single replacement or the multi-substituent on aromatic ring or the heterocycle, is respectively:
R is H, OR
1, SR
1, NR
1R
2Or YR
1R
2R
3, wherein Y is C, N, O, S or Si, R
1, R
2And R
3Identical or different, be respectively H, Boc, C
1-C
6Alkyl, halogen or C
1-C
6Haloalkyl; Boc is a tertbutyloxycarbonyl;
Perhaps R is ZCOOR
4, wherein Z is CH
2, NH, O or S, R
4Be H or C
1-C
6Alkyl substituent;
Perhaps R is halogenic substituent F, Cl, Br or I.
2. compound as claimed in claim 1 is characterized in that described X is CH, and R is H, C
1-C
6Alkoxyl group, C
1-C
6Alkyl, C
1-C
6The amido that replaces of alkyl.
3. the synthetic intermediate of compound as claimed in claim 1 or 2 is characterized in that having following structural formula:
4. the synthetic method of compound as claimed in claim 1 or 2 is characterized in that may further comprise the steps: with Pd (OAc)
2Be catalyzer, SPhos is part or do not add part, under the effect of alkali, and look unit ketone bromide and corresponding boronic acid compounds ArB (OH)
2In water-containing organic solvent, the Suzuki linked reaction took place in 2-10 hour in 30～65 ℃ of heating, and wherein Ac is an ethanoyl, Ar according to claim 1,
Described look first ketone bromide is
Described SPhos coupling part has following structural formula
Wherein Cy represents cyclohexyl.
5. synthetic method as claimed in claim 4 is characterized in that described catalyst P d (OAc)
2Mole dosage be 0.05～0.1 equivalent of look unit ketone bromide, the mole dosage of part Sphos is 0 or catalyst P d (OAc)
2Three times of mole dosage, described alkali is K
2CO
3Or Na
2CO
3, mole dosage is 1～10 equivalent of look unit ketone bromide, described water-containing organic solvent is an acetone-water.
6. synthetic method as claimed in claim 4 is characterized in that further may further comprise the steps (5), (4)～(5), (3)～(5), (2)～(5) or (1)～(5):
Synthesizing of (1) 7,8-dihydroxyl chromone: petroleum benzene triphenol and acetic acid are at BF
3OEt
280～110 ℃ of reactions obtain the phenyl ring acetylate under the catalysis, and 80～110 ℃ of cyclizations generate the chromone compound under perchloric acid and triethyl orthoformate condition again:
(2) selectivity of chromone 7-hydroxyl is exposed: behind two phenolic hydroxyl groups with caproyl protection chromogen ketone compound, utilize PhSH/ imidazoles condition in nmp solvent-10～10 ℃ the transesterification selectivity takes place exposes 7-OH and obtain following compound 4 and be used for glycosylation reaction:
(3) 8-hydroxyl-7-O-(2,3,5-three-O-ethanoyl-α-D-arabinofuranosyl) chromone is synthetic: with BF
3OEt
2Do promotor, in organic solvent, 0 ℃～room temperature compound 4 obtains the chromone glucosides with the D-pectinose to precursor reactant:
(4) bromo of chromogen ketoside-3-position: 0 ℃～room temperature is carried out bromination with the bioactive molecule bromine to the chromogen ketoside and is obtained chromone glucosides bromide in organic solvent:
(5) removing of acyl group protecting group: under the effect of alkali, chromone glucosides bromide room temperature water is separated and is obtained the naked dew product of hydroxyl in water-containing organic solvent
7. synthetic method as claimed in claim 6 is characterized in that in described each step:
The consumption of acetic acid is 0.8～1.5 equivalent of petroleum benzene triphenol mole dosage in the step (1), HC (OEt)
2Consumption is 1～10 equivalent, and the molar ratio of perchloric acid and triethyl orthoformate is 1: 2～10;
The imidazoles mole dosage is 0.2～0.5 equivalent of chromone in the step (2), is reflected in the ice-water bath and carries out, 2～4 hours reaction times;
The glycosyl donor mole dosage is 1～2 equivalent in the step (3), and the catalyzer mole dosage is 0.05～0.2 equivalent, 2～3 hours reaction times;
In the step (4) with PhI (OAc)
2The bioactive molecule bromine that/TMSBr reaction generates reacts substrate, and described organic solvent is dichloromethane solution and/or pyridine, about 8～10 hours of reaction times;
In the step (5) with K
2CO
3Make alkali, mole dosage is 2～5 equivalents, and described water-containing organic solvent is MeOH-tetrahydrofuran (THF)-H
2OK
2CO
3, reacted 2～3 hours.
8. the purposes of 3-aryl as claimed in claim 1-8-hydroxyl chromone-7-O-α-D-arabinofuranoside compound in the preparation medicine.
9. purposes as claimed in claim 8 is characterized in that being used to prepare the medicine that suppresses alpha-glucosidase activity.
10. purposes as claimed in claim 8 is characterized in that being used to prepare the medicine for the treatment of diabetes, obesity, glycosphingolipid LSD, HIV infection and tumour.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103992333A (en) * | 2014-05-28 | 2014-08-20 | 中国人民解放军军事医学科学院毒物药物研究所 | Chromone dipolymer derivative as well as preparation method and application thereof |
| CN104672192A (en) * | 2015-03-10 | 2015-06-03 | 中国药科大学 | Derivatives of isoflavones amides, as well as preparation method and medical application of derivatives |
| WO2015090201A1 (en) * | 2013-12-17 | 2015-06-25 | Versitech Limited | Use of isoflavones for the treatment of retroviral infection |
| CN105272970A (en) * | 2014-07-03 | 2016-01-27 | 中国药科大学 | Raf kinase inhibitor based on chromone structure, and preparation method and uses thereof |
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2008
- 2008-03-28 CN CN2008100353188A patent/CN101279993B/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015090201A1 (en) * | 2013-12-17 | 2015-06-25 | Versitech Limited | Use of isoflavones for the treatment of retroviral infection |
| CN103992333A (en) * | 2014-05-28 | 2014-08-20 | 中国人民解放军军事医学科学院毒物药物研究所 | Chromone dipolymer derivative as well as preparation method and application thereof |
| CN103992333B (en) * | 2014-05-28 | 2016-08-17 | 中国人民解放军军事医学科学院毒物药物研究所 | Chromone dimer derivate and its production and use |
| CN105272970A (en) * | 2014-07-03 | 2016-01-27 | 中国药科大学 | Raf kinase inhibitor based on chromone structure, and preparation method and uses thereof |
| CN104672192A (en) * | 2015-03-10 | 2015-06-03 | 中国药科大学 | Derivatives of isoflavones amides, as well as preparation method and medical application of derivatives |
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