CN103435619A - Pochonicine analogue or pharmaceutically acceptable salts of pochonicine analogue and application of pochonicine analogue or pharmaceutically acceptable salts of pochonicine analogue - Google Patents
Pochonicine analogue or pharmaceutically acceptable salts of pochonicine analogue and application of pochonicine analogue or pharmaceutically acceptable salts of pochonicine analogue Download PDFInfo
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Abstract
The invention discloses a pochonicine analogue or pharmaceutically acceptable salts of the pochonicine analogue. The pochonicine analogue can be a compound shown in the formula 1, the formula 2 or the formula 3, wherein the pochonicine analogue or the pharmaceutically acceptable salts of the pochonicine analogue have good inhibitory activity to various enzymes. Thus, the pochonicine analogue can be used as a glycosidase inhibitor and also can be applied to preparation of medicaments and pesticides.
Description
Technical field
The present invention relates to a kind of Pochonicine analogue or its pharmacy acceptable salt, and this Pochonicine analogue or its pharmacy acceptable salt are as application, this Pochonicine analogue or the application of its pharmacy acceptable salt in preparing medicine and sterilant of glycosidase inhibitor.
Background technology
Iminosugar, structurally refer to that Sauerstoffatom in sugar ring is by the analogue of a kind of monose that nitrogen-atoms replaced, due to structurally closely similar with monose, therefore can simulate monose some function ratio in vivo as the transition state by analogue enztme and Binding Capacity, thereby reach the purpose of the disease that treatment is relevant to Glycosylase, therefore, it is the important glycosidase inhibitor of a class, antiviral, antitumor, the aspects such as treatment diabetes have potential pharmacologically active ((a) St ü tz, A.E.Iminosugars as Glycosidase Inhibitors:Nojirimycin and Beyond, Wiley – VCH:Weinheim, 1999. (b) Compain, P. etc., Iminosugars:From Synthesis to Therapeutic Applications, Wiley, 2007. (c) Asano, N., Nash, R.J., Molyneux, R.J., Fleet, G.W.J.Tetrahedron:Asymmetry2000,11,1645 – 1680. (d) Watson, A.A., Fleet, G.W.J., Asano, N., Molyneux, R.J., Nash, R.J.Phytochemistry2001,56,265 – 295.).At present; two kinds of medicines as clinical use have been arranged; comprise the Beagle special (Zavesca) for the treatment of gaucher's disease and the miglitol (Miglitol) for the treatment of type ii diabetes; and the still iminosugar in clinical stage and structural modification thing thereof; butyryl radicals modifier as Celgosivir(castanospermine; the treatment hepatitis C); trihydroxyoctahydroindolizidine (swainsonine; antitumor), DAB-1(1; 4;-dideoxy-D-arabinitol, the treatment diabetes) etc. ((a) Graeme Horne; Francis X.Wilson; Jon Tinsley; David H.Williams and Richard Storer.Drug Discovery Today, In Press. (b) Bryan G.Winchester, Tetrahedron:Asymmetry2009,20,645 – 651. (c) Naoki Asano, Current Topics in Medicinal Chemistry2003,3,471-484.).
Imido carbohydrate alkaloid can be divided into pyrrolidines, piperidines, and pyrroles's mile western pyridine class, the indoles mile western pyridine class of dicyclo and remove first tropine alkanes of monocycle by its structure.Isolated first pyrroles mile western pyridine alexine(Nash since 1988, R.J.; Fellows, L.E.; Dring, J.V.; Fleet, G.W.J.; Derome, A.E.; Hamor, T.A.; Scofield, A.M.; Watkin; D.J.Tetrahedron Lett.1988; 29; 2487-2490); up to the present; pyrroles's mile western pyridine alkaloid of general existing more than 30 kind of dicyclo is separated, and the iminosugar of this class formation uniqueness is all generally inhibitor ((a) Watson, the A.A. of beta-glucosidase and alpha-glucosidase preferably; Fleet, G.W.J.; Asano, N.; Molyneux, R.J.; Nash, R.J.Phytochemistry2001,56,265-295. (b) Yamashita, T.; Yasuda, K.; Kizu, H.; Kameda, Y.; Watson, A.A.; Nash, R.J.; Fleet, G.W.J.; Asano, N.J.Nat.Prod.2002,65,1875-1881. (c) Kato, A.; Kato, N.; Adachi, I.; Hollinshead, J.; Fleet, G.W.J.; Kuriyama, C.; Ikeda, K.; Asano, N.; Nash, R.J.J.Nat.Prod.2007,70,993-997.), but be not suppress active basically to N-acetylaminohydroxyphenylarsonic acid hexosaminidase.Separate a kind of pyrroles of the poly-hydroxy with kharophen mile western pyridine alkaloid-Pochonicine in a kind of fungus culture medium β-N-ethanoyl-glucosaminidase (GlcNAcase) is had to extremely good activity (to the GlcNAcase IC in jack bean
50reach 0.288 nmole), GlcNAcase inhibitor-nagstatin that can be famous with another kind compares favourably, but Pochonicine does not have activity (Usuki, H. substantially to beta-glucosidase and alpha-glucosidase; Toyo-oka, M.; Kanzaki, H.; Okuda, T.; Nitoda, T.Bioorg.Med.Chem2009,17,7248-7253).And GlcNAcase is a kind of important enzyme in a lot of organisms; such as in insect body; GlcNAcase has participated in the chitin of the poly of (particularly cell walls) in body is hydrolyzed to glucose; for the eubolism of cell provides indispensable basic substance; therefore; the Pochonicine that optionally suppresses the activity of the GlcNAcase in insect body can be used as a kind of effective sterilant ((a) Horsch, M.; Mayer, C.; Sennhauser, U.; Rast, D.M.Pharmacol.Ther.1997,76,187-218. (b) Merzendorfer, H.; Zimoch, L.J.Exp.Biol.2003,206,4393-4412. (c) Rast, D.M.; Baumgartner, D.; Mayer, C.; Hollenstein, G.O.Phytochemistry2004,64,339-366).In mammalian body, the β that oxygen connects-N-acetylaminohydroxyphenylarsonic acid glucosaminidase (O-GlcNAcase) is being brought into play very important effect ((a) Wells, L. aspect blood sugar concentration in the monitoring control agent for another example; Vosseller, K.; Hart, G.W.Cell.Mol.Life Sci.2003,60,222-228. (b) Buse, M.G.Am.J.Physiol.Endocrinol.Metab.2006,290, E1-E8. (c) Sl á mov á, K.; Bojarov á, P.; Petr á skov á, L.;
v.Biotechnol.Adv.2010,28,682-693), so the O-GlcNAcase inhibitor is at treatment diabetes (Vosseller, K.; Wells, L.; Lane, M.D.; Hart, G.W.Proc.Natl.Acad.Sci.USA2002,99,5313-5318), alzheimer's disease ((a) Yuzwa, S.A.; Macauley, M.S.; Heinonen, J.E.; Shan, X.; Dennis, R.J.; He, Y.; Whitworth, G.E.; Stubbs, K.A.; McEachern, E.J.; Davies, G.J.; Vocadlo, D.J.Nat.Chem.Biol.2008,4,483-490. (b) Yuzwa, S.A.; Vocadlo, D.J.Curr.Alzheimer Res.2009,6,451-454) and cancer ((a) Woynarowska, B.; Wikiel, H.; Sharma, M.; Fleet, G.W.J.; Bernacki, R.J.Anticancer Res.1992,12,161-166. (b) Woynarowska, B.; Wikiel, H.; Sharma, M.; Fleet, G.W.J.; Bernacki, R.J.Proc.Amer.Assoc.Cancer Res.1989,30,91) very large using value arranged.
Therefore, need a kind of iminosugar or its pharmacy acceptable salt that suppresses preferably active that plurality of enzymes is had badly, this will bring the progress of medicine and sterilant industry.
Summary of the invention
An object of the present invention is to provide a kind of Pochonicine analogue or its pharmacy acceptable salt, this Pochonicine analogue has and suppresses preferably active plurality of enzymes.
Other purpose of the present invention is to provide application and the application in preparing medicine and sterilant as glycosidase inhibitor of described Pochonicine analogue or its pharmacy acceptable salt.
To achieve these goals, the invention provides a kind of Pochonicine analogue or its pharmacy acceptable salt, described Pochonicine analogue is compound shown in following formula 1, formula 2 or formula 3.
The present invention also provides the application as glycosidase inhibitor of described Pochonicine analogue and/or its pharmacy acceptable salt.
The present invention also provides described Pochonicine analogue and/or its pharmacy acceptable salt to prevent and/or treat the application in the medicine of diabetes in preparation.
The present invention also provides described Pochonicine analogue and/or its pharmacy acceptable salt to prevent and/or treat the application in the medicine of tumour in preparation.
The present invention also provides described Pochonicine analogue and/or its pharmacy acceptable salt to prevent and/or treat the application in the medicine of alzheimer's disease in preparation.
The present invention also provides the application of described Pochonicine analogue in preparing sterilant.
By Pochonicine analogue of the present invention or its pharmacy acceptable salt, to the inhibition active testing result of Glycosylase, can find out, this Pochonicine analogue or its pharmacy acceptable salt all have and suppress preferably active alpha-L-Rhamnosidase, β-N-ethanoyl-glucosaminidase, α-GalNAc enzyme and β-GalNAc enzyme.
Other features and advantages of the present invention will partly be described in detail in embodiment subsequently.
Embodiment
Below the specific embodiment of the present invention is elaborated.Should be understood that, embodiment described herein only, for description and interpretation the present invention, is not limited to the present invention.
The invention provides a kind of Pochonicine analogue or its pharmacy acceptable salt, described Pochonicine analogue is compound shown in following formula 1, formula 2 or formula 3.
Can prepare by following method by Pochonicine analogue of the present invention:
(i) make compound and p-cresol contact reacts shown in formula 4, formula 5 or formula 6, obtain compound shown in formula 7, formula 8 or formula 9;
(ii) make compound and methyl alcohol contact reacts shown in formula 7, formula 8 or formula 9, obtain compound shown in formula 10, formula 11 or formula 12;
(iii) make 10, compound shown in formula 11 or formula 12 carries out the hydroxyl deprotection reaction, obtains compound shown in formula 1, formula 2 or formula 3.
In the present invention, step (i) can be carried out under the first acidic substance exist in the first solvent, and the temperature of step (i) can be 25-40 ℃, and the time of step (i) can be 10-12h; Step (ii) can be carried out under the first alkaline matter exists, and step temperature (ii) can be 30-80 ℃, and the step time (ii) can be 2-4h; Step (iii) can be carried out under the second acidic substance exist in the second solvent, and step temperature (iii) can be 20-30 ℃, and the step time (iii) can be 10-12h.
In the present invention, described the first acidic substance can be at least one in zinc bromide, iron bromide, zinc chloride and trimethylsilyl trifluoromethanesulfonate, and described the first solvent can be at least one in methylene dichloride, trichloromethane and chlorobenzene; Described the first alkaline matter can be at least one in salt of wormwood, sodium carbonate and Quilonum Retard; Described the second acidic substance can be at least one in hydrochloric acid, sulfuric acid and nitric acid, and described the second solvent can be at least one in methyl alcohol, ethanol and tetrahydrofuran (THF).
Above-mentioned steps (i) and above-mentioned steps are (ii) preferably undertaken by one kettle way.
Can prepare by following method by compound shown in formula 4 of the present invention, formula 5 or formula 6:
(a) make compound shown in formula 13 or formula 14 and N-methylmorpholine-N-oxide compound contact reacts, obtain compound shown in formula 15,16 or 17;
(b) make compound and TERT-BUTYL DIMETHYL CHLORO SILANE contact reacts shown in formula 15, formula 16 or formula 17, obtain compound shown in formula 18,19 or 20;
(c) make compound shown in formula 18, formula 19 or formula 20 and Methanesulfonyl chloride in contact reacts, obtain compound shown in formula 4, formula 5 or formula 6.
In the present invention, step (a) can be carried out under the first catalyzer exists in the 3rd solvent, and the temperature of step (a) can be 20-25 ℃, and the time of step (a) can be 96-154h; Step (b) can be carried out under the second alkaline matter and the second catalyzer exist in the 4th solvent, and the temperature of step (b) can be-5-5 ℃, and the time of step (b) can be 8-10h; Step (c) can be carried out under the 3rd alkaline matter exists in the 5th solvent, and the temperature of step (c) can be-5-5 ℃, and the time of step (c) can be 1-2h.
In the present invention, described the first catalyzer can be perosmic anhydride, and described the 3rd solvent can be at least one in acetone, butanone and isobutyl methyl ketone; Described the second alkaline matter can be at least one in triethylamine, diisopropylamine and diisopropylethylamine, described the second catalyzer can be at least one in DMAP, sodium iodide and tetrabutylammonium iodide, and described the 4th solvent can be at least one in methylene dichloride, trichloromethane and chlorobenzene; Described the 3rd alkaline matter can be at least one in triethylamine, diisopropylamine and diisopropylethylamine, and described the 5th solvent can be at least one in methylene dichloride, trichloromethane and chlorobenzene.
Above-mentioned steps (a) and above-mentioned steps (b) are preferably undertaken by one kettle way.
Can prepare by following method by compound shown in formula 13 of the present invention or formula 14:
(1) make compound shown in formula 21 and trimethylsilyl cyanide contact reacts, obtain compound shown in formula 22;
(2) make compound shown in formula 22 and hydrogen contact reacts, obtain compound shown in formula 23;
(3) make compound shown in formula 23 and tert-Butyl dicarbonate contact reacts, obtain compound shown in formula 24;
(4) make compound shown in formula 24 and diacetyl oxide contact reacts, obtain compound shown in formula 25;
(5) make compound shown in formula 25 and formic acid contact reacts, obtain compound shown in formula 26;
(6) make compound shown in formula 26 and Dai Si-Martin's oxygenant contact reacts, obtain compound shown in formula 27;
(7) make compound shown in formula 27 and zinc and allyl bromide 98 contact reacts, obtain compound shown in formula 28 and formula 29;
(8) make compound and diacetyl oxide contact reacts shown in formula 28 and formula 29, obtain compound shown in formula 13 and formula 14.
In the present invention, step (1) can be carried out in the 6th solvent, and the temperature of step (1) can be 20-30 ℃, and the time of step (1) can be 10-12h; Step (2) can be carried out under the 3rd catalyzer exists in the 7th solvent, and the temperature of step (2) can be 20-30 ℃, and the time of step (2) can be 24-72h; Step (3) can be carried out in the 8th solvent, and the temperature of step (3) can be 20-30 ℃, and the time of step (3) can be 24-72h; Step (4) can be carried out under the 4th alkaline matter exists in the 9th solvent, and the temperature of step (4) can be-78-30 ℃, and the time of step (4) can be 1-3h; Step (5) is carried out in the tenth solvent, and the temperature of step (5) can be-5-30 ℃, and the time of step (5) can be 0.5-1h; Step (6) can be carried out under the 5th alkaline matter exists in the 11 solvent, and the temperature of step (6) can be 20-30 ℃, and the time of step (6) can be 1-5h; Step (7) can be carried out under the 3rd acidic substance exist in the 12 solvent, and the temperature of step (7) can be 50-60 ℃, and the time of step (7) can be 3-6h; Step (8) can be deposited at hexabasic property material and the 4th catalyzer, under in the 13 solvent, carry out, the temperature of step (8) can be 20-30 ℃, the time of step (8) can be 8-10h.
In the present invention, described the 6th solvent can be at least one in methyl alcohol, ethanol and tetrahydrofuran (THF); Described the 3rd catalyzer can be at least one in thunder niobium nickel, palladium carbon (Pd/C) and palladium hydroxide, and described the 7th solvent can be at least one in methyl alcohol, ethanol and tetrahydrofuran (THF); Described the 8th solvent can be at least one in methyl alcohol, ethanol and tetrahydrofuran (THF); Described the 4th alkaline matter can be at least one in diisopropylamine-n-Butyl Lithium, diisopropylamine-tert-butyl lithium and diisopropylamine-s-butyl lithium, and described the 9th solvent can be at least one in methyl alcohol, ethanol and tetrahydrofuran (THF); Described the tenth solvent can be at least one in ether, propyl ether and propylene glycol monomethyl ether; Described the 5th alkaline matter can be at least one in sodium bicarbonate, saleratus and lithium bicarbonate, and described the 11 solvent can be at least one in methylene dichloride, trichloromethane and chlorobenzene; Described the 3rd acidic substance can be at least one in ammonium chloride, brometo de amonio and ammonium nitrate, and described the 12 solvent can be at least one in methyl alcohol, ethanol and tetrahydrofuran (THF); Described hexabasic property material can be at least one in triethylamine, pyridine and quadrol, described the 4th catalyzer can be at least one in DMAP, pyridine and tetrabutylammonium iodide, described the 13 solvent can be at least one in methylene dichloride, tetrahydrofuran (THF) and Isosorbide-5-Nitrae-dioxane.
Above-mentioned steps (1) is not preferably carried out under the reactive gas atmosphere at argon gas or nitrogen etc.
Above-mentioned steps (2) and above-mentioned steps (3) are preferably undertaken by one kettle way.
Above-mentioned steps (4) is not preferably carried out under the reactive gas atmosphere at argon gas or nitrogen etc.
Above-mentioned steps (6) and above-mentioned steps (7) preferably repeat 8-12 time by one kettle way.
The method according to this invention, described method can also comprise isolates next step reactant from every step reaction products therefrom.The process of described separation can be implemented according to the method for purification of this area routine, such as thinking column chromatography, distillation method, extraction process, recrystallization method etc.
The present invention also provides the application as glycosidase inhibitor of described Pochonicine analogue and/or its pharmacy acceptable salt.
The present invention also provides described Pochonicine analogue and/or its pharmacy acceptable salt to prevent and/or treat the application in the medicine of diabetes in preparation.
The present invention also provides described Pochonicine analogue and/or its pharmacy acceptable salt to prevent and/or treat the application in the medicine of tumour in preparation.
The present invention also provides described Pochonicine analogue and/or its pharmacy acceptable salt to prevent and/or treat the application in the medicine of alzheimer's disease in preparation.
The present invention also provides the application of described Pochonicine analogue in preparing sterilant.
Below will describe the present invention by preparation example and embodiment.
In the present invention, the NMR spectrogram is measured by your AV300 type NMR spectrometer with superconducting magnet of Brooker, and wherein, deuterated reagent is deuterochloroform (CDCl
3) or deuterated methanol (CD
3oD), the hydrogen spectrum be take tetramethylsilane as interior mark, and carbon is composed with CDCl
3(δ=77.0) are interior mark; Fusing point is measured by Tyke, Beijing melting point apparatus.
The 200-300 order silicagel column that column chromatography is used is purchased from Yantai Chemical Industry Research Inst.; The tlc silica gel plate GF that TLC uses is purchased from Yantai Chemical Industry Research Inst..
In the situation that do not make any Special Statement, agents useful for same of the present invention and solvent all through standard method (with reference to " and reagent purifying handbook) use after purifying.
In the present invention, shown in formula 21 prepared by compound by the following method.
Under ice bath to fill L-ribose (purchased from Beijing the victory Hua Teng Science and Technology Ltd.) (50.0g, 0.333mol) the 1L single port bottle of dry acetone (100mL) in splash into 2,2-Propanal dimethyl acetal (purchased from victory Hua Teng Science and Technology Ltd. in Beijing) (27.1mL, 0.40mol), add again tosic acid (5.74g, 0.0334mol), after stirring 15 minutes, remove ice bath, change under 25 ℃ and stir 2h.TLC detects raw material and substantially disappears, and adds sodium bicarbonate solid (5.60g, 0.0668mol) to continue to stir.Recording pH with the pH test paper is 8, stop stirring, and suction filtration, concentrating under reduced pressure can obtain 56.4g colourless syrup 1.
Gained colourless syrup 1 is dissolved in methylene dichloride (200mL), be cooled to 0 ℃ in ice bath, add successively triethylamine (62.0mL, 0.45mol) and triphenylmethyl chloride (purchased from Beijing chemical reagent company limited) (107.7g, 0.39mol) stir 15 minutes, remove ice bath, change at 25 ℃ and stir 12h.TLC detects raw material and substantially disappears, and adds water (500.0mL) cancellation reaction, separates organic phase and water, organic phase washes (3 * 100.0mL) with water three times, dichloromethane extraction three times (3 * 100.0mL) for water, merge organic phase, with saturated common salt, washes once (100mL).Add dried over mgso 0.5h, suction filtration, be spin-dried for and obtain 122.0g colourless syrup 2.
Gained colourless syrup 2 is dissolved in methylene dichloride (200mL), adds successively triethylamine (58mL, 0.42mol) and oxammonium hydrochloride (purchased from Beijing chemical reagent company limited) (27.2g, 0.39mol), this mixture is heated to back flow reaction 20h.TLC detects raw material and substantially disappears, and is cooled to 25 ℃, adds water (100mL) cancellation, separate organic phase and water, organic phase washes (3 * 300.0mL) with water three times, dichloromethane extraction three times (3 * 50.0mL) for water, merge organic phase, with saturated common salt, wash once (100.0mL).Organic phase dried over mgso 0.5h, suction filtration, be spin-dried for and obtain 119.2g colourless syrup 3.
Colourless syrup 3 is dissolved in methylene dichloride (200mL), under 0 ℃, adds successively triethylamine (56.3mL, 0.41mol) and TERT-BUTYL DIMETHYL CHLORO SILANE (purchased from victory Hua Teng Science and Technology Ltd. in Beijing) (52.5g, 0.35mol).React 24h at 25 ℃ again after adding material, TLC detects raw material and substantially disappears, add water (100mL) cancellation, separate organic phase and water, organic phase washes (3 * 100.0mL) with water three times, dichloromethane extraction three times (3 * 50.0mL) for water, merge organic phase, with saturated common salt, washes once (100.0mL).Organic phase dried over mgso 0.5h, suction filtration, be spin-dried for and obtain 136.5g colourless syrup 4.
Gained colourless syrup 4 is dissolved in methylene dichloride (200mL); under 0 ℃; add successively triethylamine (50.7mL; 0.36mol) and methyl sulphonyl chlorine (purchased from victory Hua Teng Science and Technology Ltd. in Beijing) (26.3mL; 0.32mol) reaction 2h; TLC detects raw material and substantially disappears; add water (100mL) cancellation; separate organic phase and water; organic phase washes (3 * 100.0mL) with water three times; dichloromethane extraction three times (3 * 50.0mL) for water, merge organic phase, with saturated common salt, washes once (100.0mL).Organic phase dried over mgso 0.5h, suction filtration, be spin-dried for, and obtains 133.1g buff syrup 5.
Gained buff syrup 5 is dissolved in toluene (200mL), under 0 ℃, add tetra-n-butyl Neutral ammonium fluoride hydrate (purchased from victory Hua Teng Science and Technology Ltd. in Beijing) (57.6g, 0.22mol) reaction 1h after, transfer in oil bath and be heated to back flow reaction 1h, after TLC plate monitoring reaction is complete, solvent is spin-dried for and obtains the tawny syrup during question response cool to room temperature, add ethyl acetate (200mL) and water (80mL) extraction, organic phase washes (3 * 50.0mL) with water three times, dichloromethane extraction three times (3 * 50.0mL) for water, merge organic phase, wash once (100.0mL) with saturated common salt.Organic phase dried over mgso 0.5h, suction filtration, be spin-dried for, and crosses column purification and obtain the light brown solid 6 of 47g.
Above-mentioned light brown solid 6 is carried out to fusing point and nuclear magnetic resonance spectroscopy, and result is as follows:
Fusing point: 85-87 ℃.
1H?NMR(300MHz,CDCl
3):δ(ppm)7.50–7.21(m,15H),5.32(d,J=6.0Hz,1H),4.98(t,J=6.0Hz,1H),4.12(dd,J=6.0and3.0Hz,1H),3.94(dd,J=9.0and3.0Hz,1H),3.67(t,J=9.0,1H),1.38(s,3H),1.26(s,3H)；
13C?NMR(75MHz,CDCl
3):δ(ppm)143.8,132.4,129.0,127.9,127.3,111.9,87.4,75.1,74.2,59.0,27.3,26.3。
By above-mentioned analytical results, can prove, the light brown solid 6 of gained is compound shown in formula 21.
Preparation example 1
By compound 45.0g(0.105mol shown in formula 21) be dissolved in methyl alcohol 200mL, add trimethylsilyl cyanide (purchased from Aladdin reagent company limited) 16.8mL(0.126mol under argon shield), stir 15h under 25 ℃.After TLC detects raw material and substantially disappears, concentrating under reduced pressure obtains faint yellow solid 47g, and this faint yellow solid is obtained to white solid 39.5g with methyl alcohol and sherwood oil recrystallization purifying, filtration.
Above-mentioned white solid is carried out to nuclear magnetic resonance spectroscopy, and result is as follows:
1H?NMR(300MHz,CDCl
3):δ(ppm)7.30-7.21(m,15H),5.30(m,1H),4.85-4.77(m,2H),4.28(s,1H),3.56(dd,J=8.7and7.5Hz,1H),3.42(dd,J=9.0and5.7Hz,1H),3.21(dd,J=12.3and5.7Hz,1H),1.28(s,3H),1.27(s,3H)；
13C?NMR(75MHz,CDCl
3):δ(ppm)143.8,128.8,127.9,127.2,114.8,112.4,87.3,78.8,77.6,67.9,62.5,60.9,25.6,24.9。
By above-mentioned analytical results, can prove, the gained white solid is compound shown in formula 22.
By compound 10.00g(0.022mol shown in formula 22) be dissolved in tetrahydrofuran (THF) 25.0mL and methyl alcohol 2.5mL, add successively tert-Butyl dicarbonate (purchased from Beijing the victory Hua Teng Science and Technology Ltd.) 12.00g(0.055mol) and thunder niobium nickel 6.0g(purchased from Dalian general chemical industry company limited), by hydrogen exchange three times of the air in reaction flask, and then, under atmosphere of hydrogen, under 25 ℃, stir 72h.After TLC detection raw material disappears substantially, filtered and recycled thunder niobium nickel, concentrated filtrate, obtain the thick product of light yellow oily, and the thick product of gained obtains white solid 12.57g through column chromatographic isolation and purification (ethyl acetate/petroleum ether=1/8).
Above-mentioned white solid is carried out to fusing point and nuclear magnetic resonance spectroscopy, and result is as follows:
Fusing point: 76-77 ℃.
1H?NMR(300MHz,CDCl
3):δ(ppm)7.50-7.47(m,6H),7.31-7.19(m,9H),4.91-4.79(m,1H),4.54-4.47(m,1H),3.88-3.78(m,1H),3.59-3.55(m,1H),3.47-3.21(m,3H),3.07(m,1H),1.45-1.41(m,13H),1.37-1.34(m,3H),1.28-1.26(m,7H)；
13C?NMR(75MHz,CDCl
3):δ(ppm)156.1,154.3,153.1,144.4,144.2,144.1,144.0,128.9,127.7,126.9,112.7,112.6,111.3,111.1,87.0,86.8,86.7,82.9,82.8,81.4,80.1,79.2,68.0,64.6,61.3,60.5,53.5,53.4,40.3,38.6,28.5,28.3,28.2,27.7,27.6,26.5。
By above-mentioned analytical results, can prove, the gained white solid is compound shown in formula 24.
Under argon shield; in the there-necked flask of 250mL, add in tetrahydrofuran (THF) 100mL; add again diisopropylamine 13.3mL(0.095mol); be cooled to-78 ℃; dropwise add n-Butyl Lithium (being purchased from lark prestige reagent company limited) 35.4mL(0.089mol); stir 0.25h under-78 ℃; then drip compound 28.4g(0.04mol shown in the formula 24 that is dissolved in tetrahydrofuran (THF) 30mL); stir 0.25h after adding under-78 ℃; then add fast diacetyl oxide 12.6mL(0.14mol); vigorous stirring 0.25h, then stir 0.25h in ice-water bath.After TLC monitoring raw material no longer reduces, add saturated ammonium chloride solution cancellation reaction, be stirred to the solution clarification, be extracted with ethyl acetate, separate organic phase and water, organic phase washes (3 * 100mL) with water three times, water is extracted with ethyl acetate (3 * 50mL) three times, merge organic phase, wash once (100mL) with saturated common salt again, after organic phase is used dried over mgso 0.5h, suction filtration, concentrated filtrate obtains the oily crude product, and the gained crude product obtains colorless oil 21.8g through column chromatographic isolation and purification (ethyl acetate/petroleum ether=1/10).
Above-mentioned colorless oil is carried out to nuclear magnetic resonance spectroscopy, and result is as follows:
1H?NMR(300MHz,CDCl
3):δ(ppm)7.51-7.48(m,6H),7.30-7.19(m,9H),4.98-4.95(m,1H),4.40-4.33(m,2H),3.93-3.52(m,4H),2.44(s,3H),1.44-1.22(m,24H)；
13C?NMR(75MHz,CDCl
3):δ(ppm)173.5,173.0,154.0,152.8,144.4,129.0,127.6,126.8,112.3,111.2,86.8,83.4,81.0,79.7,62.8,60.1,42.6,29.1,28.3,28.0,27.7,26.9,26.6,25.5,22.7。
By above-mentioned analytical results, can prove, the gained white solid is compound shown in formula 25.
By compound 20.6g(0.03mol shown in formula 25) be dissolved in ether 400mL, in ice-water bath cooling 2 minutes, add 400mL formic acid, within 2 minutes, the recession deicing is bathed, and under 25 ℃, reacts 0.5h.After TLC detection raw material disappears substantially, add ethyl acetate 200mL dilution, add sodium bicarbonate 500g under ice-water bath.Add again ethyl acetate 500mL dilution, solution is poured into to separating funnel, water is separated with organic phase, then add saturated sodium bicarbonate solution 500ml in organic phase, then separate organic phase and water, until organic phase is neutral.Water is extracted with ethyl acetate, and adds in saturated sodium bicarbonate 100ml and organic phase.Merge organic phase, saturated aqueous common salt for organic phase (100mL) washing, after adding anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure, the adularescent solid generates.Add sherwood oil and a small amount of ether, cross and filter out white solid, rinse solid with bulk petroleum ether and a small amount of anhydrous diethyl ether, filtrate obtains the colorless oil crude product through concentrating under reduced pressure, and the gained crude product obtains colorless oil 27.6g through column chromatographic isolation and purification (ethyl acetate/petroleum ether=1/10).
Above-mentioned colorless oil is carried out to nuclear magnetic resonance spectroscopy, and result is as follows:
1H?NMR(300MHz,CDCl
3):δ(ppm)5.20-5.13(m,1H),4.71-4.67(m,1H),4.49-4.45(m,1H),4.42-4.35(m,1H),3.92-3.89(m,2H),3.82-3.75(m,2H),3.70-3.64(m,1H),2.48(s,3H),1.55(s,9H),1.46(s,9H),1.40(s,3H),1.28(s,3H)；
13C?NMR(75MHz,CDCl
3):δ(ppm)172.5,155.4,152.6,111.2,84.1,80.7,80.3,79.7,76.7,63.9,62.2,61.0,42.9,28.2,27.9,27.0,26.1,24.7。
By above-mentioned analytical results, can prove, the gained colorless oil is compound shown in formula 26.
By Dai Si-Martin's oxygenant (purchased from victory Hua Teng Science and Technology Ltd. in Beijing) 13.95g(0.033mol) be dissolved in methylene dichloride 150ml, add again sodium bicarbonate 4.1g(0.049mol), then drip compound 27.3g(0.0165mol shown in the formula 26 that is dissolved in methylene dichloride 50ml), stir 0.33h at 25 ℃ after adding.After TLC detection raw material disappears substantially, add the ether dilution, add saturated sodium thiosulfate solution 100ml under ice-water bath, stir to clarify at 25 ℃.Settled solution washes (3 * 50mL) with water three times, wash (2 * 50mL) twice with saturated ammonium chloride solution again, dichloromethane extraction three times (3 * 20mL) for water, merge organic phase, organic phase is washed once (100mL) with saturated sodium-chloride again, anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure obtain the colorless oil crude product, and this head product, without crossing column purification, directly drops into next step reaction.
Above-mentioned colorless oil crude product is dissolved in tetrahydrofuran (THF) 100ml, add respectively again the zinc powder 5.4g(0.083mol activated) and allyl bromide 98 (purchased from victory Hua Teng Science and Technology Ltd. in Beijing) 2.9mL(0.033mol), dropwise add saturated ammonium chloride solution, the reaction very exothermic, the question response heat release slows down, then repeats above operation 10 times.After TLC detection raw material substantially no longer reduces, suction filtration, filtrate is washed (2 * 100mL) twice with saturated ammonium chloride solution, washes with water twice (2 * 100mL), saturated sodium-chloride is washed (2 * 100mL) twice, and anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure obtain colorless oil.Gained oily matter obtains white solid 2.0g and colorless oil 3.4g through column chromatographic isolation and purification (ethyl acetate/petroleum ether=1/10).
Above-mentioned white solid is carried out to nuclear magnetic resonance spectroscopy, and result is as follows:
1H?NMR(300MHz,CDCl
3):δ(ppm)6.16-6.02(m,1H),5.97(s,1H),5.19-5.08(m,2H),4.59(dd,J=5.7and3.9Hz,1H),4.51(dd,J=9.3and6.3Hz,1H),4.28-4.26(m,2H),3.78-3.63(m,2H),3.46(dd,J=8.4and2.7Hz,1H),2.68-2.63(m,1H),2.49(s,3H),2.43-2.33(m,1H),1.54(s,9H),1.44(s,9H),1.38(s,3H),1.27(s,3H)；
13C?NMR(75MHz,CDCl
3):δ(ppm)172.3,155.3,152.5,135.2,116.3,111.0,83.8,80.6,80.0,79.5,67.5,67.0,63.4,42.6,37.8,28.1,27.8,27.0,26.4,24.8。
By above-mentioned analytical results, can prove, the gained white solid is compound shown in formula 28.
Above-mentioned colorless oil is carried out to nuclear magnetic resonance spectroscopy, and result is as follows:
1H?NMR(300MHz,CDCl
3):δ(ppm)6.04-5.90(m,1H),5.14-5.04(m,2H),4.80-4.77(m,1H),4.65-4.64(m,1H),4.39-4.37(m,1H),4.25(m,1H),3.96(dd,J=13.5and7.2Hz,1H),3.82(m,1H),3.69(dd,J=21.6and8.1Hz,1H),2.48(m,4H),2.26(m,1H),1.56(s,9H),1.49(s,12H),1.29(s,3H)；
13C?NMR(75MHz,CDCl
3):δ(ppm)172.7,155.7,152.6,136.2,115.8,111.3,83.8,80.6,79.3,76.8,69.5,65.3,61.7,43.1,38.3,28.1,27.9,26.8,25.7,24.0。
By above-mentioned analytical results, can prove, the gained colorless oil is compound shown in formula 29.
Preparation example 2
By compound 1.8g(3.7mmol shown in formula 28) be dissolved in pyridine 10ml, DMAP 180mg(is purchased from Beijing chemical reagent company limited respectively) and diacetyl oxide 0.7mL(7.4mmol), stir 0.25h under 25 ℃.After TLC detection raw material disappears substantially, the reaction solution concentrating under reduced pressure, gained solution is dissolved in ethyl acetate (20mL), washes with water three times (3 * 20.0mL), and water is extracted with ethyl acetate (3 * 20.0mL) three times, merge organic phase, and wash once with saturated nacl aqueous solution, organic phase dried over mgso 0.5h, filter, the concentrated crude product that obtains of filtrate decompression, crude product obtains colourless oil liquid 1.9g through column chromatographic isolation and purification (ethyl acetate/petroleum ether=1/8).
Above-mentioned colorless oil is carried out to nuclear magnetic resonance spectroscopy, and result is as follows:
1H?NMR(300MHz,CDCl
3):δ(ppm)5.89-5.78(m,2H),5.11-5.02(m,2H),4.67-4.64(m,1H),4.36-4.33(m,1H),4.25-4.20(m,1H),4.01(m,1H),3.93-3.89(m,1H),3.85-3.78(m,1H),2.60-2.55(m,2H),2.48(s,3H),2.05(s,3H),1.56(s,9H),1.47(s,3H),1.45(s,3H),1.28(s,3H)；
13C?NMR(75MHz,CDCl
3):δ(ppm)173.0,170.1,153.8,152.7,134.6,116.9,112.0,83.5,80.3,80.0,79.2,76.8,71.0,61.9,60.7,42.8,35.9,29.5,28.1,27.8,26.8,26.0,24.5,21.0。
By above-mentioned analytical results, can prove, the gained colorless oil is compound shown in formula 13.
By compound 1.90g(3.6mmol shown in formula 13) be dissolved in acetone 20.0mL, be transferred in 100mL single port bottle, add again perosmic anhydride aqueous solution 10ml(0.5%), then add N-methylmorpholine-N-oxide compound 0.71mL(3.6mmol), stir 96h under 25 ℃.After TLC detects the raw material disappearance, add saturated sodium sulfite solution 20ml cancellation reaction, stir 1h under 25 ℃, concentrating under reduced pressure obtains water-soluble crude product, crude product is through dichloromethane extraction, drying, suction filtration, concentrating under reduced pressure obtain colorless oil crude product 2.00g, and the gained crude product is directly dropped into to next step reaction.
Previous step gained colorless oil crude product 2.00g is dissolved in methylene dichloride 10ml, add successively DMAP 44mg(0.36mmol) and triethylamine 1.5mL(10.7mmol), finally add TERT-BUTYL DIMETHYL CHLORO SILANE (1.08g, 7.14mmol), under 25 ℃, stir 4h.After TLC detection raw material disappears substantially, add water 5ml cancellation reaction, separate organic phase and water, organic phase washes (3 * 20.0mL) with water three times, dichloromethane extraction three times (3 * 20.0mL) for water, merge organic phase, with saturated nacl aqueous solution, washes once (50.0mL).Organic phase anhydrous magnesium sulfate drying 0.5h, filtration, the concentrated colorless oil crude product that obtains of filtrate decompression, gained colorless oil crude product obtains 1.40g colourless oil liquid 1 and 0.63g colourless oil liquid 2 through column chromatographic isolation and purification (ethyl acetate/petroleum ether=1/6).
Above-mentioned colourless oil liquid 1 is carried out to nuclear magnetic resonance spectroscopy, and result is as follows:
1H?NMR(300MHz,CDCl
3):δ(ppm)6.02(m,1H),4.66-4.62(m,1H),4.35-4.33(m,1H),4.27-4.25(m,1H),3.96-3.93(m,2H),3.77-3.73(m,1H),3.62-3.58(m,1H),3.54-3.52(m,2H),2.48(s,3H),2.08(s,3H),2.05-2.02(m,1H),1.84-1.77(m,1H),1.60(s,1H),1.56-1.54(m,9H),1.45(s,12H),1.27(s,3H),0.92-0.89(m,9H),0.10-0.05(m,6H)；
13C?NMR(75MHz,CDCl
3):δ(ppm)172.9,171.0,154.0,152.7,111.9,83.7,80.4,79.8,79.6,69.8,69.1,68.6,67.4,67.0,63.5,62.4,61.2,59.4,42.8,35.8,28.2,27.9,26.9,26.1,25.8,25.6,24.5,21.1,18.2,-3.6,-5.5。
By above-mentioned analytical results, can prove, the gained colorless oil is compound shown in formula 18.
Above-mentioned colourless oil liquid 2 is carried out to nuclear magnetic resonance spectroscopy, and result is as follows:
1H?NMR(300MHz,CDCl
3):δ(ppm)5.91(s,1H),4.72-4.68(m,1H),4.35-4.33(m,1H),4.26-4.23(m,1H),4.00-3.95(m,2H),3.79-3.78(m,2H),3.62(dd,J=9.9and3.9Hz,1H),3.39(dd,J=9.9and7.8Hz,1H),2.69(m,1H),2.48(s,3H),2.07-2.05(m,3H),2.03-1.96(m,1H),1.88-1.77(m,1H),1.56-1.54(m,9H),1.46-1.45(m,12H),1.27-1.24(m,3H),0.92-0.89(m,9H),0.10-0.06(m,6H)；
13C?NMR(75MHz,CDCl
3):δ(ppm)173.0,170.5,153.9,152.7,112.0,83.6,80.1,80.0,79.5,72.8,70.2,70.0,68.4,67.2,63.5,63.4,62.2,61.1,42.9,34.7,28.2,27.9,26.9,26.5,26.1,25.8,25.6,24.5,21.2,18.2,-3.6,-5.5。
By above-mentioned analytical results, can prove, the gained colorless oil is compound shown in formula 19.
Preparation example 3
By compound 2g(4.1mmol shown in formula 29) be dissolved in pyridine 10ml, DMAP 200mg(is purchased from Beijing chemical reagent company limited respectively) and diacetyl oxide 0.7mL(8.2mmol), stir 0.25h under 25 ℃.After TLC detection raw material disappears substantially, the reaction solution concentrating under reduced pressure, gained solution is dissolved in ethyl acetate (20mL), washes with water three times (3 * 20.0mL), and water is extracted with ethyl acetate (3 * 20.0mL) three times, merge organic phase, and wash once with saturated nacl aqueous solution, organic phase dried over mgso 0.5h, filter, the concentrated crude product that obtains of filtrate decompression, crude product obtains colourless oil liquid 2.1g through column chromatographic isolation and purification (ethyl acetate/petroleum ether=1/8).
Above-mentioned colorless oil is carried out to the fusing point nuclear magnetic resonance spectroscopy, and result is as follows:
Fusing point: 85-86 ℃.
1H?NMR(300MHz,CDCl
3):δ(ppm)5.91-5.75(m,2H),5.15-5.03(m,2H),4.75-4.72(m,1H),4.36-4.34(m,2H),4.03-3.96(m,1H),3.83-3.80(m,1H),3.74-3.68(m,1H),2.65-2.51(m,2H),2.47(s,3H),2.02(s,3H),1.55(s,9H),1.46(s,12H),1.28(s,3H)；
13C?NMR(75MHz,CDCl
3):δ(ppm)172.3,169.4,153.7,152.4,134.2,116.8,111.3,83.2,79.6,79.2,76.9,70.2,62.0,61.7,42.7,36.2,27.9,27.7,26.6,25.8,24.5,20.8。
By above-mentioned analytical results, can prove, the gained colorless oil is compound shown in formula 14.
By compound 2.1g(4.0mmol shown in formula 14) be dissolved in acetone 20.0mL, be transferred in 100mL single port bottle, add again perosmic anhydride aqueous solution 10ml(0.5%), then add N-methylmorpholine-N-oxide compound 0.71mL(4.0mmol), stir 96h under 25 ℃.After TLC detects the raw material disappearance, add saturated sodium sulfite solution 20ml cancellation reaction, stir 1h under 25 ℃, concentrating under reduced pressure obtains water-soluble crude product, crude product is through dichloromethane extraction, drying, suction filtration, concentrating under reduced pressure obtain colorless oil crude product 2.2g, and the gained crude product is directly dropped into to next step reaction.
Previous step gained colorless oil crude product 2.2g is dissolved in methylene dichloride 10ml, add successively DMAP 48mg(0.40mmol) and triethylamine 1.5mL(10.7mmol), finally add TERT-BUTYL DIMETHYL CHLORO SILANE (1.19g, 7.85mmol), under 25 ℃, stir 4h.After TLC detection raw material disappears substantially, add water 5ml cancellation reaction, separate organic phase and water, organic phase washes (3 * 20.0mL) with water three times, dichloromethane extraction three times (3 * 20.0mL) for water, merge organic phase, with saturated nacl aqueous solution, washes once (50.0mL).Organic phase anhydrous magnesium sulfate drying 0.5h, filtration, the concentrated colorless oil crude product that obtains of filtrate decompression, gained colorless oil crude product obtains the 647mg colourless oil liquid through column chromatographic isolation and purification (ethyl acetate/petroleum ether=1/6).
Above-mentioned colourless oil liquid is carried out to nuclear magnetic resonance spectroscopy, and result is as follows:
1H?NMR(300MHz,CDCl
3):δ(ppm)5.81(s,1H),5.22-5.15(m,1H),4.75-4.74(m,1H),4.36-4.29(m,2H),3.99-3.94(m,1H),3.91-3.88(m,2H),3.78-3.72(m,2H),3.67-3.63(m,1H),3.51-3.45(m,1H),2.48-2.47(m,3H),2.05-2.04(m,3H),1.99-1.95(m,1H),1.76-1.67(m,1H),1.55(s,9H),1.48-1.45(m,12H),1.26(s,3H),0.90-0.88(m,9H),0.07-0.04(s,6H)；
13C?NMR(75MHz,CDCl
3):δ(ppm)172.7,170.4,170.2,153.9,152,7,130.7,128.7,111.6,111.3,83.8,83.5,80.7,80.1,79.7,79.4,79.2,73.4,69.8,69.4,67.0,66.8,64.1,62.9,61.8,43.0,42.9,35.3,34.4,31.7,30.4,29.5,29.3,29.2,28.9。
By above-mentioned analytical results, can prove, the gained colorless oil is compound shown in formula 20.
Preparation example 4
By compound 1.20g(1.78mmol shown in formula 18) be dissolved in methylene dichloride 5ml, add triethylamine 0.5mL(3.56mmol under ice-water bath is cooling), more dropwise add Methanesulfonyl chloride 0.22mL, (2.67mmol), under 0 ℃, stir 0.5h.After TLC detection raw material disappears substantially, add water 2ml cancellation, separate organic phase and water, organic phase washes (3 * 15.0mL) with water three times, and dichloromethane extraction three times (3 * 15.0mL) for water merges organic phase, wash once (30.0mL) with saturated nacl aqueous solution again, add anhydrous magnesium sulfate drying 0.5h, suction filtration, concentrating under reduced pressure obtain the colorless oil crude product, and gained colorless oil crude product obtains colorless oil 1.31g through column chromatographic isolation and purification.
Above-mentioned colourless oil liquid is carried out to nuclear magnetic resonance spectroscopy, and result is as follows:
1H?NMR(300MHz,CDCl
3):δ(ppm)5.98(m,1H),4.73(m,1H),4.68-4.64(m,1H),4.36-4.34(m,1H),3.97-3.83(m,1H),3.79-3.71(m,3H),3.14(m,1H),3.10-3.06(m,2H),2.48(s,3H),2.42-2.38(m,1H),2.11-2.03(m,4H),1.58-1.55(m,6H),1.47(m,10H),1.27-1.26(m,8H),0.89(s,9H),0.07(s,6H)；
13C?NMR(75MHz,CDCl
3):δ(ppm)173.0,170.6,153.9,152,7,111.9,83.8,80.5,79.8,79.5,68.7,65.3,62.0,60.1,42.8,38.2,32.7,31.5,29.5,28.2,27.9,26.9,26.1,25.8,24.4,22.5,21.0,18.2,14,0,-5.6。
By above-mentioned analytical results, can prove, the gained colorless oil is compound shown in formula 4.
By compound 290mg(0.386mmol shown in formula 4) be dissolved in methylene dichloride (5.0mL), add zinc bromide 519mg(2.32mmol in solution), then add p-cresol 167mg(1.54mmol), 12h stirred under 25 ℃.After TLC detection raw material disappears substantially, add saturated sodium bicarbonate solution 10ml cancellation reaction, suction filtration, filtrate water is washed (3 * 10.0mL) three times, and dichloromethane extraction three times (3 * 10.0mL) for water merges organic phase, saturated sodium-chloride is washed once (20.0mL), anhydrous magnesium sulfate drying 0.5h, suction filtration, filtrate obtain crude product through concentrating under reduced pressure, and crude product is directly dropped into to next step.
The previous step crude product is dissolved in methyl alcohol 3mL, add salt of wormwood 107mg(0.772mmol), add again a small amount of water (0.5mL), stir 10h under 25 ℃, after TLC detects the raw material primitive reaction, concentrating under reduced pressure, the gained oily liquids adds methylene dichloride to dissolve, wash with water three times (3 * 10mL), dichloromethane extraction three times (3 * 10mL) for organic phase, merge organic phase, then wash once with the 50mL saturated nacl aqueous solution, anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure, the gained crude product obtains colorless oil 67mg through column chromatographic isolation and purification.
Above-mentioned colourless oil liquid is carried out to nuclear magnetic resonance spectroscopy, and result is as follows:
1H?NMR(300MHz,CDCl
3):δ(ppm):6.41(s,1H),4.70–4.66(m,1H),4.54–4.51(m,1H),4.41(dd,J=6.0and3.0Hz,1H),3.47–3.44(m,1H),3.41–3.33(m,2H),3.31–3.28(m,2H),3.26–3.17(m,1H),3.07–2.98(m,1H),2.14(s,1H),2.07–1.98(m,1H),1.89(s,3H),1.72–1.64(m,1H),1.46(s,3H),1.23(s,3H),0.83(s,9H),0.00(s,6H)；
13C?NMR(75MHz,CDCl
3):δ(ppm):170.2,113.0,85.6,82.3,73.3,69.9,69.1,68.8,64.5,40.4,38.6,26.6,26.0,23.8,23.3,18.5,-5.1
By above-mentioned analytical results, can prove, the gained colorless oil is compound shown in formula 10.
By compound 45.0mg(0.11mmol shown in formula 10) be dissolved in methyl alcohol 1mL, add 3mol/L hydrochloric acid 1mL, stir 12h under 25 ℃, removal of solvent under reduced pressure, add ammoniacal liquor in the crude product after concentrated, concentrating under reduced pressure again, after repeating aforesaid operations three times, obtain colorless oil 27.5mg by crude product through the acidic ion exchange resin column separating purification.
Above-mentioned colourless oil liquid is carried out to nuclear magnetic resonance spectroscopy, and result is as follows:
1H?NMR(300MHz,CD
3OD):δ(ppm)4.48–4.47(m,1H),4.30(t,J=6.0Hz,1H),3.81(t,J=6.0Hz,1H),3.62–3.56(m,1H),3.54–3.52(m,1H),3.47–3.41(m,1H),3.37–3.34(m,3H),3.10(dd,J=11.1and5.4Hz,1H),2.06(ddd,J=12.0,6.0and3.0Hz,1H),1.97(s,3H),1.79(ddd,J=12.0,6.0and3.0Hz,1H)；
13C?NMR(75MHz,CD
3OD):δ(ppm)173.7,76.6,74.1,73.9,71.5,70.8,68.7,66.2,42.8,39.8,22.6
By above-mentioned analytical results, can prove, the gained colorless oil is compound shown in formula 1.
Preparation example 5
By compound 1.0g(1.48mmol shown in formula 19) be dissolved in methylene dichloride 5ml, add triethylamine 0.42mL(2.97mmol under ice-water bath is cooling), more dropwise add Methanesulfonyl chloride 0.18mL, (2.22mmol), under 0 ℃, stir 0.5h.After TLC detection raw material disappears substantially, add water 2ml cancellation, separate organic phase and water, organic phase washes (3 * 15.0mL) with water three times, and dichloromethane extraction three times (3 * 15.0mL) for water merges organic phase, wash once (30.0mL) with saturated nacl aqueous solution again, add anhydrous magnesium sulfate drying 0.5h, suction filtration, concentrating under reduced pressure obtain the colorless oil crude product, and gained colorless oil crude product obtains colorless oil 1.02g through column chromatographic isolation and purification.
Above-mentioned colourless oil liquid is carried out to nuclear magnetic resonance spectroscopy, and result is as follows:
1H?NMR(300MHz,CDCl
3):δ(ppm)4.70–4.62(m,2H),4.34–4.32(m,1H),4.26(m,1H),3.91–3.88(m,3H),3.72–3.65(m,2H),3.15–3.07(m,3H),2.49–2.47(m,3H),2.42–2.32(m,1H),2.11(s,3H),2.08–2.01(m,1H),1.60–1.55(m,9H),1.46–1.42(m,9H),1.27–1.26(m,6H),0.89(s,9H),0.07–0.06(m,6H)；
13C?NMR(75MHz,CDCl
3):δ(ppm)173.0,172.6,170.4,169.9,153.8,152.5,152.3,112.7,111.5,84.5,83.7,83.5,83.1,80.5,80.1,79.5,79.4,72.6,71.8,69.7,42.7,37.9,33.8,31.4,29.4,28.0,27.7,26.8,25.9,25.7,25.6,24.2,20.9,18.1,-5.7
By above-mentioned analytical results, can prove, the gained colorless oil is compound shown in formula 5.
By compound 300mg(0.40mmol shown in formula 5) be dissolved in methylene dichloride (5.0mL), add zinc bromide 537mg(2.4mmol in solution), then add p-cresol 173mg(1.59mmol), 12h stirred under 25 ℃.After TLC detection raw material disappears substantially, add saturated sodium bicarbonate solution 10ml cancellation reaction, suction filtration, filtrate water is washed (3 * 10.0mL) three times, and dichloromethane extraction three times (3 * 10.0mL) for water merges organic phase, saturated sodium-chloride is washed once (20.0mL), anhydrous magnesium sulfate drying 0.5h, suction filtration, filtrate obtain crude product through concentrating under reduced pressure, and crude product is directly dropped into to next step.
The previous step crude product is dissolved in methyl alcohol 3mL, add salt of wormwood 111mg(0.799mmol), add again a small amount of water (0.5mL), stir 10h under 25 ℃, after TLC detects the raw material primitive reaction, concentrating under reduced pressure, the gained oily liquids adds methylene dichloride to dissolve, wash with water three times (3 * 10mL), dichloromethane extraction three times (3 * 10mL) for organic phase, merge organic phase, with the 50mL saturated nacl aqueous solution, wash once again, anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure, the gained crude product obtains colorless oil 70mg shown in formula 11 through column chromatographic isolation and purification.It should be noted that shown in formula 11, compound is very unstable, needs one are purified, drop into immediately next step reaction, so be difficult to obtain about the spectral data of compound shown in formula 11.
By compound 50.0mg(0.12mmol shown in formula 11) be dissolved in methyl alcohol 1mL, add 3mol/L hydrochloric acid 1mL, stir 12h under 25 ℃, removal of solvent under reduced pressure, add ammoniacal liquor in the crude product after concentrated, concentrating under reduced pressure again, after repeating aforesaid operations three times, obtain colorless oil 30mg by crude product through the acidic ion exchange resin column separating purification.
Above-mentioned colourless oil liquid is carried out to nuclear magnetic resonance spectroscopy, and result is as follows:
1H?NMR(300MHz,CD
3OD):δ(ppm)4.46(dd,J=10.8and5.1Hz,1H),4.21(t,J=4.0Hz,1H),4.00(dd,J=12.0and7.5Hz,1H),3.83(dd,J=7.8and3.9Hz,1H),3.76(dd,J=12.0and3.9Hz,1H),3.58(m,2H),3.49–3.44(m,2H),3.40–3.35(m,1H),2.14(dt,J=12.6and6.3Hz,1H),2.01(s,3H),1.97–1.88(m,1H)；
13C?NMR(75MHz,CD
3OD):δ(ppm)173.7,78.7,73.9,73.7,68.9,63.3,62.5,61.6,43.6,40.8,22.6。
By above-mentioned analytical results, can prove, the gained colorless oil is compound shown in formula 2.
Preparation example 6
By compound 200mg(0.27mmol shown in formula 6) be dissolved in methylene dichloride (5.0mL), add zinc bromide 358mg(1.6mmol in solution), then add p-cresol 115mg(1.06mmol), 12h stirred under 25 ℃.After TLC detection raw material disappears substantially, add saturated sodium bicarbonate solution 10ml cancellation reaction, suction filtration, filtrate water is washed (3 * 10.0mL) three times, and dichloromethane extraction three times (3 * 10.0mL) for water merges organic phase, saturated sodium-chloride is washed once (20.0mL), anhydrous magnesium sulfate drying 0.5h, suction filtration, filtrate obtain crude product through concentrating under reduced pressure, and crude product is directly dropped into to next step.
The previous step crude product is dissolved in methyl alcohol 3mL, add salt of wormwood 74mg(0.53mmol), add again a small amount of water (0.5mL), stir 10h under 25 ℃, after TLC detects the raw material primitive reaction, concentrating under reduced pressure, the gained oily liquids adds methylene dichloride to dissolve, wash with water three times (3 * 10mL), dichloromethane extraction three times (3 * 10mL) for organic phase, merge organic phase, with the 50mL saturated nacl aqueous solution, wash once again, anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure, the gained crude product obtains colorless oil 48.1mg shown in formula 11 through column chromatographic isolation and purification.
Above-mentioned colourless oil liquid is carried out to nuclear magnetic resonance spectroscopy, and result is as follows:
1H?NMR(300MHz,CDCl
3):δ(ppm):6.25(s,1H),4.54–4.51(m,1H),4.33–4.32(m,2H),3.51–3.32(m,7H),2.72–2.63(m,1H),2.51–2.41(m,1H),1.87(s,3H),1.50–1.45(m,1H),1.34(s,3H),1.36(s,3H),0.82(s,9H),0.00(s,6H)；
13C?NMR(75MHz,CDCl
3):δ(ppm):170.1,112.1,86.1,81.5,75.8,72.1,69.0,68.4,66.4,40.9,38.5,26.3,26.0,25.8,23.5,23.3,18.5,-5.2。
By above-mentioned analytical results, can prove, the gained colorless oil is compound shown in formula 12.
By compound 30.0mg(0.07mmol shown in formula 12) be dissolved in methyl alcohol 1mL, add 3mol/L hydrochloric acid 1mL, stir 12h under 25 ℃, removal of solvent under reduced pressure, add ammoniacal liquor in the crude product after concentrated, concentrating under reduced pressure again, after repeating aforesaid operations three times, obtain colorless oil 17.8mg by crude product through the acidic ion exchange resin column separating purification.
Above-mentioned colourless oil liquid is carried out to nuclear magnetic resonance spectroscopy, and result is as follows:
1H?NMR(300MHz,CD
3OD):δ(ppm)4.57(ddd,J=3.4,5.0and6.5Hz,1H),3.99(t,J=3.9Hz,1H),3.81(dd,J=8.7and3.6Hz,1H),3.62-3.55(m,2H),3.44–3.43(m,2H),3.39–3.35(m,1H),3.16–3.13(m,1H),2.92(dt,J=8.9and4.7Hz,1H),2.29(dt,J=13.3and7.0Hz,1H),1.98(s,3H),1.66(dt,J=11.4and5.8Hz,1H)；
13C?NMR(75MHz,CD
3OD):δ(ppm)173.9,76.9,76.5,72.4,71.4,70.7,69.7,65.9,42.3,39.0,22.6。
By above-mentioned analytical results, can prove, the gained colorless oil is compound shown in formula 3.
In following examples, dynamics research carries out in the 50mM Trisodium Citrate/phosphoric acid buffer of 37 ℃.According to the difference of matrix, the enzyme concn of preparation is 0.1-0.5mg/mL.It is matrix that active testing be take 4-nitrophenol pyranoside, under the optimum activity pH of every kind of enzyme, is tested.Matrix, enzyme solution and inhibitor (compound and Pochonicine shown in formula 1 of the present invention, formula 2 or formula 3) are cultivated 30 minutes under 37 ℃, then in ultraviolet-visible pectrophotometer, started reaction, measure its absorption to the 400nm wavelength light.Finally use the GraFit program carry out data analysis (specifically referring to Leatherbarrow, R.J.Grafit4.0; ErithacusSoftware:Staines, UK, 1998.).4-nitrophenol pyranoside matrix, alpha-L-Rhamnosidase, β-N-ethanoyl-glucosaminidase, α-GalNAc enzyme and β-GalNAc enzyme are purchased from Sigma-Aldrich.
Embodiment 1
Compound shown in the formula 1 made by preparation example 4 is carried out to the test of Glycosylase inhibition, and result is as shown in table 1.In table 1, IC
50mean to make the concentration of the activity inhibited of enzyme to the required inhibitor of a half, unit is μ M; Numerical value is the inhibiting rate of inhibitor concentration while being 1000 μ M in bracket.
Embodiment 2
Compound shown in the formula 2 made by preparation example 5 is carried out to the test of Glycosylase inhibition, and result is as shown in table 1.
Embodiment 3
Compound shown in the formula 3 made by preparation example 6 is carried out to the test of Glycosylase inhibition, and result is as shown in table 1.
Table 1
Inhibition active testing result by table 1 can be found out; Pochonicine analogue of the present invention or its pharmacy acceptable salt all have and suppress preferably active alpha-L-Rhamnosidase, β-N-ethanoyl-glucosaminidase, α-GalNAc enzyme and β-GalNAc enzyme, can apply as glycosidase inhibitor.
β-N-ethanoyl-glucosaminidase is had preferably and to suppress active explanation Pochonicine analogue of the present invention and can prevent and/or treat application (reference: Vosseller, K. in the medicine of diabetes in preparation; Wells, L.; Lane, M.D.; Hart, G.W.Proc.Natl.Acad.Sci.USA2002,99,5313-5318).
β-N-ethanoyl-glucosaminidase is had preferably and to suppress active explanation Pochonicine analogue of the present invention and can prevent and/or treat application (reference: (a) Woynarowska, B. in the medicine of tumour in preparation; Wikiel, H.; Sharma, M.; Fleet, G.W.J.; Bernacki, R.J.Anticancer Res.1992,12,161-166. (b) Woynarowska, B.; Wikiel, H.; Sharma, M.; Fleet, G.W.J.; Bernacki, R.J.Proc.Amer.Assoc.Cancer Res.1989,30,91).
β-N-ethanoyl-glucosaminidase is had preferably and to suppress active explanation Pochonicine analogue of the present invention and can prevent and/or treat application (reference: (a) Yuzwa, S.A. in the medicine of alzheimer's disease in preparation; Macauley, M.S.; Heinonen, J.E.; Shan, X.; Dennis, R.J.; He, Y.; Whitworth, G.E.; Stubbs, K.A.; McEachern, E.J.; Davies, G.J.; Vocadlo, D.J.Nat.Chem.Biol.2008,4,483-490. (b) Yuzwa, S.A.; Vocadlo, D.J.Curr.Alzheimer Res.2009,6,451-454).
β-N-ethanoyl-glucosaminidase is had to the Pochonicine analogue of the present invention of the active explanation of inhibition preferably and can in preparing sterilant, apply (reference: (a) Horsch, M.; Mayer, C.; Sennhauser, U.; Rast, D.M.Pharmacol.Ther.1997,76,187-218. (b) Merzendorfer, H.; Zimoch, L.J.Exp.Biol.2003,206,4393-4412. (c) Rast, D.M.; Baumgartner, D.; Mayer, C.; Hollenstein, G.O.Phytochemistry2004,64,339-366).
More than describe the preferred embodiment of the present invention in detail; but the present invention is not limited to the detail in above-mentioned embodiment, in technical conceive scope of the present invention; can carry out multiple simple variant to technical scheme of the present invention, these simple variant all belong to protection scope of the present invention.
It should be noted that in addition each the concrete technical characterictic described in above-mentioned embodiment, in reconcilable situation, can be combined by any suitable mode.For fear of unnecessary repetition, the present invention is to the explanation no longer separately of various possible array modes.
In addition, between various embodiment of the present invention, also can carry out arbitrary combination, as long as it is without prejudice to thought of the present invention, it should be considered as content disclosed in this invention equally.
Claims (7)
1. a Pochonicine analogue or its pharmacy acceptable salt, is characterized in that, described Pochonicine analogue is compound shown in following formula 1, formula 2 or formula 3.
2. Pochonicine analogue claimed in claim 1 and/or its pharmacy acceptable salt are as the application of glycosidase inhibitor.
3. application according to claim 2; wherein; described Glycosylase is alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase enzymes, alpha-Mannosidase, beta-Mannosidase, alpha-L-fucosidase, beta-glucuronidase, α, at least one in α-trehalase, alpha-L-Rhamnosidase, α-N-ethanoyl-glucosaminidase, β-N-ethanoyl-glucosaminidase, α-GalNAc enzyme and β-GalNAc enzyme.
4. Pochonicine analogue claimed in claim 1 and/or its pharmacy acceptable salt prevent and/or treat the application in the medicine of diabetes in preparation.
5. Pochonicine analogue claimed in claim 1 and/or its pharmacy acceptable salt prevent and/or treat the application in the medicine of tumour in preparation.
6. Pochonicine analogue claimed in claim 1 and/or its pharmacy acceptable salt prevent and/or treat the application in the medicine of alzheimer's disease in preparation.
7. the application of Pochonicine analogue claimed in claim 1 in preparing sterilant.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5021427A (en) * | 1988-12-23 | 1991-06-04 | The Board Of Regents, The University Of Texas System | Novel pyrrolizidine alkaloid |
| CN1761666A (en) * | 2003-01-23 | 2006-04-19 | Mnl药品有限公司 | Polyhydroxylated pyrrolizidine |
| WO2006077427A2 (en) * | 2005-01-21 | 2006-07-27 | Mnl Pharma Limited | Antiviral drug combinations |
| WO2010015816A2 (en) * | 2008-08-06 | 2010-02-11 | Summit Corporation Plc | Treatment of lysosomal storage disorders and other proteostatic diseases |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5021427A (en) * | 1988-12-23 | 1991-06-04 | The Board Of Regents, The University Of Texas System | Novel pyrrolizidine alkaloid |
| CN1761666A (en) * | 2003-01-23 | 2006-04-19 | Mnl药品有限公司 | Polyhydroxylated pyrrolizidine |
| WO2006077427A2 (en) * | 2005-01-21 | 2006-07-27 | Mnl Pharma Limited | Antiviral drug combinations |
| WO2010015816A2 (en) * | 2008-08-06 | 2010-02-11 | Summit Corporation Plc | Treatment of lysosomal storage disorders and other proteostatic diseases |
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