CN106810563B - Furans card mountain alkane forskolin and its pharmaceutical composition and its application in pharmacy - Google Patents
Furans card mountain alkane forskolin and its pharmaceutical composition and its application in pharmacy Download PDFInfo
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Abstract
Furans card mountain alkane forskolin shown in formula (I), using it as the pharmaceutical composition of effective component, preparation method and its application in preparation prevention and treatment diabetes and metabolic disease drug.Pharmacological activity test proves: the compound of the present invention 1-13 has significant inhibiting effect to hepatic gluconeogenic.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular, to furans card mountain alkane forskolin, it is effective using it as drug
The pharmaceutical composition of ingredient, they are preparing the application in the drug for preventing and treating diabetes B and metabolic disease.
Background technique
Diabetes (diabetes mellitus, DM) be caused by insulin deficiency and (or) insulin resistance it is chronic
Metabolic disease.In recent years, ascendant trend is presented always in diabetes morbidity, counts (International Diabetes Federation according to authoritative institution
IDF, 2015 annual datas), global diabetic in 2015 is up to 4.15 hundred million, wherein 80% or more is distributed in developing country, in advance
Counting this number of the year two thousand forty will be up to 6.42 hundred million.With the improvement of living standards and lifestyle change, diabetes mellitus in China illness rate is sharply
Rising, data are also shown, and diabetes mellitus in China number of patients in 2015 is up to 1.09 hundred million, and illness rate occupies first place in the world close to 10%,
Have become the chronic disease for seriously endangering China citizen health.Diabetes have become the third after cardiovascular and cerebrovascular disease and tumour
Big non-communicable diseases is current one of the principal disease for seriously endangering human health.
Diabetes are broadly divided into two classes, type 1 diabetes (insulin-dependent diabetes mellitus, IDDM) and diabetes B (non-pancreas
Island element dependent diabetes, NIDDM).Wherein, diabetes B accounts for about the 90-95% or more of diabetes general population.It uses at present
Mainly there is insulin sensitizer (thiazolidinediones) in the oral drugs for the treatment of diabetes B, promote insulin secretion medicine (sulphur
Uride and non-sulfonylurea), biguanide drug and alpha-glucosidase restrainer.In addition, DPPIV inhibitor class drug, GLP-1 class
It is to list the antidiabetic object used in the past 10 years like species drug, SGLT2 inhibitor class drug.
Studies have shown that leading diabetogenic main pathological basis is hypoinsulinism, insulin resistance and endogenous Portugal
The output of grape sugar increases, before the meal and postprandial hyperglycemia so as to cause diabetic.The medicine of current clinically application for the treatment of diabetes
Object is primarily directed to hypoinsulinism and improves insulin resistance.Melbine (metformin) is current clinical unique
The drug of endogenous glucose output is reduced for non-substantivity.It is to make that existing research, which shows that endogenous glucose generates increase,
The main reason for being increased at diabetic's fasting blood-glucose.Endogenous glucose is mainly derived from liver, hepatic glucose production
Mainly by being endogenously synthesized glucose, i.e. gluconeogenesis.Therefore, effectively inhibit the excessive gluconeogenesis of liver, reduce endogenous
Property glucose generate, for maintain normal glycemic levels be of great significance, be treat diabetes B one of important target.
Medicinal plant be find anti-diabetic activity ingredient valuable source, in recent years therefrom discovery various structures activity at
Point, including flavones, lignanoid, diterpene, triterpene compound etc., it is expected to exploitation and clinically applies.Card mountain alkane Diterpenes chemical combination
Object have extensive bioactivity, such as antitumor, antibacterial, anti-inflammatory, anti-malarial function (Wu, et.al.,
ChemistryBiodiversity,2011,8,1370‐1399).But furans card mountain alkane diterpene-kind compound there is no to control at present
The report of treat and prevent diabetes and metabolic disease etc..
Summary of the invention
It is an object of the invention to: a new class of furans card mountain alkane forskolin and phangininE and its derivative are provided
Object, using it as the pharmaceutical composition of active constituent, preparation method and such compound and its pharmaceutical composition are being prepared in advance
Application in the drug of anti-and treatment diabetes B and metabolic disease.
In order to realize above-mentioned purpose of the invention, the present invention provides the following technical solutions:
Furans card mountain alkane forskolin shown in formula (I),
In formula, X is selected from O or NH；
R1Selected from hydrogen, methyl, aldehyde radical, carboxyl, methylol (- CH2OH), methylene halogen (halogen is fluorine, chlorine, bromine), C1‐10
Alkoxymethylene, C2‐10Acyl-oxygen methylene ,-COOR, wherein R is C2‐10Alkyl, isocyanate group ,-NHCONR2, wherein R
For H and C1‐10Alkyl or H and C2‐10Acyl group is all C1‐10Alkyl ,-CH2NH2/‐CH2NR2, wherein R is H and C1‐10Alkyl or H and
C2‐10Acyl group is all C1‐10Alkyl；
R2、R3It is respectively selected from H, carbonyl, C1‐10Alkoxy；
The furans card mountain alkane forskolin as shown in formula (I) is the furans Ladanum alkane diterpene as shown in following formula (II)
Derivative,
In formula, X is selected from O or NH；
R is selected from hydrogen, methyl, aldehyde radical, carboxyl, methylol (- CH2OH), methylene halogen (halogen is fluorine, chlorine, bromine), C1‐10
Alkoxymethylene, C2‐10Acyl-oxygen methylene ,-COOR, wherein R is C2‐10Alkyl, isocyanate group ,-NHCONR2, wherein R
For H and C1‐10Alkyl or H and C2‐10Acyl group is all C1‐10Alkyl ,-CH2NH2/‐CH2NR2, wherein R is H and C1‐10Alkyl or H and
C2‐10Acyl group is all C1‐10Alkyl；
The furans card mountain alkane forskolin as shown in formula (I) is Ka Shan shown in following structural formula (IV) and formula (V)
Alkane forskolin,
In formula, R is selected from hydrogen, methyl, aldehyde radical, carboxyl, methylol (- CH2OH), methylene halogen (halogen be fluorine, chlorine,
Bromine), C1‐10Alkoxymethylene, C2‐10Acyl-oxygen methylene ,-COOR, wherein R is C2‐10Alkyl, isocyanate group ,-
NHCONR2, wherein R is H and C1‐10Alkyl or H and C2‐10Acyl group is all C1‐10Alkyl ,-CH2NH2/‐CH2NR2, wherein R be H and
C1‐10Alkyl or H and C2‐10Acyl group is all C1‐10Alkyl；
Furans Ladanum alkane diterpene as shown above is following compound:
Furans card mountain alkane diterpene phangininE and its derivative and its medicine for active constituent shown in following formula (VI)
Application of the compositions in the drug that preparation treats or prevents diabetes B or metabolic disease,
Wherein, R1And R2Selected from hydrogen, hydroxyl, methoxyl group or carbonyl, work as R1For carbonyl, R2When for hydrogen atom, compound is
phanginin E；Work as R2For carbonyl, R1When for hydrogen atom, compound is 19-deoxo-20-oxophanginin E.
The present invention provides the pharmaceutical composition for treating or preventing diabetes and metabolic disease, wherein containing therapeutically effective amount
Above-mentioned furans card mountain alkane forskolin and pharmaceutical acceptable carrier.
The present invention provides above-mentioned furans card mountain alkane forskolins or its pharmaceutical composition to treat or prevent 2 types in preparation
Application in the drug of diabetes.
The present invention provides above-mentioned furans card mountain alkane forskolins or its pharmaceutical composition to treat or prevent generation in preparation
Application in the drug of thanking property disease.
The present invention provides phanginin E answering in the drug for treating or preventing diabetes B or metabolic disease
With.
Invention also provides 19-deoxo-20-oxophanginin E to treat or prevent diabetes B or metabolism
Application in the drug of property disease.
The present invention still further provides the preparation method of the furans card mountain alkane diterpene compound 1-13, and this method includes
Following step:
The preparation of compound P1 and P2:
Bush seed 10kg is extracted three times with 95% ethyl alcohol in soaking at room temperature, 48 hours every time, combined extract after crushing
Crude extract is concentrated under reduced pressure to obtain, crude extract is dispersed in water, is extracted four times with isometric ethyl acetate, extraction is concentrated under reduced pressure
Liquid, through silica gel column chromatography, column chromatographs and is recrystallized to give compound P1 and P2 to acetic acid ethyl ester extract repeatedly；
The preparation of compound 1 and 2:
Compound P1 is dissolved in 10mL methanol solvate, and p-methyl benzenesulfonic acid is added, in room temperature reaction 8h, the water into reaction solution
15mL is extracted with ethyl acetate, and organic phase is washed with saturation NaCl, and anhydrous sodium sulfate is dry, and pale yellow powder is concentrated under reduced pressure to obtain,
Through silica gel column chromatography petroleum ether: acetone=8:2 obtains compound 1 and compound 2；
The preparation of compound 3 and 4:
Compound P2 is dissolved in 20mL methanol solvate, and p-methyl benzenesulfonic acid 64mg is added, in room temperature reaction 8h, into reaction solution
Water 20mL, is extracted with ethyl acetate, and organic phase is washed with saturation NaCl, and anhydrous sodium sulfate is dry, and yellowish toner is concentrated under reduced pressure to obtain
End.Through silica gel column chromatography petroleum ether: acetone=8:2 obtains compound 3 and compound 4；
The preparation of compound 5:
Compound P1 is dissolved in 2mL dichloromethane solvent, PDC31mg and 4A molecular sieve 31mg is added, in reacting at room temperature
Night, reaction solution are filtered with diatomite, and reduced pressure is evaporated, and obtain faint yellow solid, through silica gel column chromatography petroleum ether: ethyl acetate=
8:2 obtains compound 5；
The preparation of compound 6:
Compound P2 is dissolved in 3mL dichloromethane solvent, PDC90mg and 4A molecular sieve 90mg is added, in reacting at room temperature
Night, reaction solution are filtered with diatomite, and reduced pressure is evaporated, and obtain faint yellow solid.Through silica gel column chromatography petroleum ether: ethyl acetate=
8:2 obtains compound 6；
The preparation of compound 7:
Compound 1 is dissolved in 9mL tetrahydrofuran solvent, and LiAlH is added440mg heats reaction 4h, Xiang Fanying at 75 DEG C
5% sulfuric acid solution of 1mL is added in liquid to stir 5 minutes, is extracted with ethyl acetate, extract liquor washs 3 with saturated sodium bicarbonate solution
Secondary, anhydrous sodium sulfate is dry, and faint yellow solid is concentrated under reduced pressure to obtain.Through silica gel column chromatography petroleum ether: ethyl acetate=9:1ization
Close object 7；
The preparation of compound 8:
Compound 7 is dissolved in 5mL dichloromethane solvent, under condition of ice bath be added 200 μ L of acetic anhydride, 200 μ L of triethylamine,
DMAP 3.0mg is then raised to room temperature reaction 2h naturally, and reaction solution is diluted with water, and water phase is extracted with ethyl acetate, and extract liquor is used
Saturated sodium chloride solution is washed 3 times, and anhydrous sodium sulfate is dry, and faint yellow solid is concentrated under reduced pressure to obtain, through silica gel column chromatography petroleum ether:
Ethyl acetate=20:1 obtains compound 8；
The preparation of compound 9:
Compound 4 is dissolved in 6mL tetrahydrofuran solvent, and LiAlH is added430mg heats reaction 4h, Xiang Fanying at 75 DEG C
5% sulfuric acid solution of 1mL is added in liquid to stir 5 minutes, is extracted with ethyl acetate, extract liquor washs 3 with saturated sodium bicarbonate solution
Secondary, anhydrous sodium sulfate is dry, faint yellow solid is concentrated under reduced pressure to obtain, through silica gel column chromatography petroleum ether: ethyl acetate=9:1ization
Close object 9；
The preparation of compound 10:
Compound 9 is dissolved in 5mL dichloromethane solvent, 100 μ L of acetic anhydride, 100 μ of triethylamine are added under condition of ice bath
L, DMAP1.5mg is then raised to room temperature reaction 2h naturally, and reaction solution is diluted with water, and water phase is extracted with ethyl acetate, and extract liquor is used
Saturated sodium chloride solution is washed 3 times, and anhydrous sodium sulfate is dry, and faint yellow solid is concentrated under reduced pressure to obtain, through silica gel column chromatography petroleum ether:
Ethyl acetate=20:1 obtains compound 10；
The preparation of compound 11:
Compound P2 is dissolved in 6mL tetrahydrofuran solvent, and LiAlH is added430mg heats reaction 4h, Xiang Fanying at 75 DEG C
5% sulfuric acid solution of 1mL is added in liquid to stir 5 minutes, is extracted with ethyl acetate, extract liquor washs 3 with saturated sodium bicarbonate solution
Secondary, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and the sample after concentration continues to be dissolved in 5mL dichloromethane solvent, and IBX is added
300mg is added appropriate saturated sodium bicarbonate solution, is extracted with ethyl acetate 3 times in room temperature reaction 12h, and aqueous sodium persulfate is dry, subtracts
Pressure is concentrated to give faint yellow solid, and through silica gel column chromatography petroleum ether: ethyl acetate=8:2 obtains compound 11；
The preparation of compound 12:
Compound 9 is dissolved in 2mL dichloromethane solvent, and IBX 100mg is added in room temperature reaction 12h, appropriate saturation is added
Sodium bicarbonate solution is extracted with ethyl acetate 3 times, and aqueous sodium persulfate is dry, faint yellow solid is concentrated under reduced pressure to obtain, through silica gel column chromatography
Petroleum ether: ethyl acetate=8:2 obtains compound 12；
The preparation of compound 13:
Compound P1 20mg is dissolved in 6mL tetrahydrofuran solvent, and KOH10mg is added and heats reaction 3h at 75 DEG C, cooling
To room temperature, 1mL 1N hydrochloric acid solution is added into reaction solution and stirs 5 minutes, is extracted with ethyl acetate, extract liquor unsaturated carbonate
Hydrogen sodium solution washs 3 times, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and the sample after concentration continues to be dissolved in 5mL dichloromethane solvent
In, PDC 30mg is added in room temperature reaction 12h, appropriate saturated sodium bicarbonate solution is added, is extracted with ethyl acetate 3 times, water sulphur
Sour sodium is dry, faint yellow solid is concentrated under reduced pressure to obtain, through silica gel column chromatography petroleum ether: ethyl acetate=8:2 obtains compound 13.
It when compound in the present invention is used as drug, can directly use, or be used in the form of pharmaceutical composition.?
The form that compound can be formed with other drugs uses, which contains 0.1~99%, preferably 0.5~90%
The compounds of this invention, to be pharmaceutically acceptable, nontoxic to humans and animals and inert pharmaceutical preparation is commonly medicinal for remaining
Carrier and/or excipient.Pharmaceutical composition of the invention is used in the form of per weight dose.It can be used different
Solid pharmaceutical preparation (tablet, capsule, granule, powder etc.) is made in pharmaceutic adjuvant.
Unless otherwise indicated, terminology used in the present invention " alkyl " refers to the saturation monovalent hydrocarbon of straight chain or branch,
Middle alkyl can be optionally substituted by one or more substituents.The straight chain C that the present invention uses1‐6With branch C3‐6Alkyl is also claimed
For " low alkyl group ".The embodiment of alkyl include but is not limited to methyl, ethyl, propyl (including all isomeric forms),
N- propyl, isopropyl, butyl (including all isomeric forms), n- butyl, isobutyl group, t- butyl, amyl are (including all same
Divide isomeric form) and hexyl (including all isomeric forms).For example, C1‐6Alkyl refers to the straight chain with 1 to 6 carbon atoms
It is saturated monovalent hydrocarbon or the branch with 3 to 6 carbon atoms is saturated monovalent hydrocarbon.
Unless otherwise indicated, terminology used in the present invention " acyl group " refers to linear chain or branched chain, cyclic annular or non-annularity saturation
The phosphinylidyne or sulfonyl that alkyl replaces are also possible to the phosphinylidyne or sulfonyl of the substitution of the unsaturated alkyls such as alkenyl, alkynyl, aryl.
Unless otherwise mentioned, terminology used in the present invention " alkenyl " refer to the straight chain comprising one or more carbon-carbon double bonds or
Person's branch monovalent hydrocarbon.Alkenyl can be optionally substituted by one or more substituents.Term " alkenyl " also includes " cis-
And " E " and " Z " formula structure for being understood of the group of " trans- (trans) " structure or those of ordinary skill in the art (cis) ".
Unless otherwise mentioned, terminology used in the present invention " alkenyl " includes straight chain and branched-chain alkenyl.For example, C2‐6Alkenyl refers to 2 to 6
The branch unsaturation monovalent hydrocarbon of the straight chain unsaturation monovalent hydrocarbon of carbon atom or 3 to 6 carbon atoms.
Unless otherwise mentioned, terminology used in the present invention " alkynyl " refer to the straight chain comprising one or more triple carbon-carbon bonds or
Person's branch monovalent hydrocarbon.Alkynyl can be optionally substituted by one or more substituents.Unless otherwise mentioned, term " alkynyl "
Including straight chain and branch alkynyl.
Unless otherwise mentioned, terminology used in the present invention " aryl " refers to monocyclic aryl and/or comprising at least one fragrance
The polycyclic monovalent aryl of hydrocarbon ring.
Unless otherwise mentioned, terminology used in the present invention " miscellaneous alkyl ", " miscellaneous thiazolinyl " and " miscellaneous alkynyl " refer respectively to one
Or alkyl, alkenyl and alkynyl that multiple carbon atoms are replaced by hetero atom.
Unless otherwise mentioned, terminology used in the present invention " hetero atom " refers to other any originals other than carbon or hydrogen
Son.It is often referred to N, O, S, Si or P.
Detailed description of the invention
Fig. 1 is the Activity Results figure of furans card mountain alkane forskolin of the invention to hepatic gluconeogenesis inhibiting effect.
Fig. 2 is furans card mountain alkane forskolin structural schematic diagram of the invention.
Specific embodiment
Below in conjunction with attached drawing, embodiment through the invention further illustrates essentiality content of the invention, but not
Limit the present invention in any form.
Embodiment 1:
Specific experiment method of the invention:
Compound P1 and P2 be from pick up from Baise of Guangxi produce pulse family marble platymiscium bush (Caesalpiniasappan) second
It is isolated in alcohol extracting thing.
The preparation of compound P1 and P2:
Bush (C.sappan) seed 10kg is extracted three times with 95% ethyl alcohol in soaking at room temperature, 48 hours every time after crushing,
Crude extract (450g) is concentrated under reduced pressure to obtain in combined extract.Crude extract is dispersed in water, with isometric ethyl acetate extraction four
It is secondary, extract liquor is concentrated under reduced pressure.Through silica gel column chromatography, column chromatographs and is recrystallized to give chemical combination to acetic acid ethyl ester extract (200g) repeatedly
Object P1 (15g) and P2 (6g).
Embodiment 2:
The preparation of compound 1 and 2
Compound P1 (100mg) is dissolved in 10mL methanol solvate, is added p-methyl benzenesulfonic acid (32mg), in room temperature reaction 8h.
The water 15mL into reaction solution, is extracted with ethyl acetate, and organic phase is washed with saturation NaCl, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure
Obtain pale yellow powder.Compound 1 (70mg, yield 67%) and compound are obtained through silica gel column chromatography (petroleum ether: acetone=8:2)
2 (12mg, yields 11%).
Compound 1: white powder；1H NMR(500MHz,CDCl3)δ:7.22(1H,br s),6.20(1H,br s),
4.41 (1H, br s), 4.17 (1H, dd, J=11.7,2.5Hz), 3.69 (1H, dd, J=11.7,1.3Hz), 3.67 (3H, s),
3.27 (3H, s), 2.72 (1H, dd, J=15.4,5.1Hz), 2.58 (1H, m), 2.23-2.40 (3H, m), 2.09 (1H, m),
1.68-2.08 (3H, m), 1.66 (1H, m), 1.53-1.62 (2H, m), 1.45 (1H, td, J=11.7,5.1Hz), 1.36 (1H,
M), 1.24 (1H, m), 1.16 (1H, m), 0.96 (3H, d, J=7.1Hz)13C NMR(125MHz,CDCl3)δ:175.8(s),
149.5(s),140.4(d),122.5(s),109.8(d),103.9(d),61.7(t),54.6(q),51.5(q),45.5(s),
45.5(d),42.3(d),38.9(s),38.0(t),36.8(d),35.5(t),31.5(d),29.5(t),23.5(t),22.5
(t), 21.1 (t), 16.9 (q) cation ESIMS m/z397 [M+Na]+；HRESIMS m/z397.1988[M+Na]+(calcd
for C22H30O5Na,397.1991).
Compound 2: white powder；1H NMR(500MHz,CDCl3)δ:7.22(1H,br s),6.17(1H,br s),
4.81 (1H, br s), 4.29 (1H, dd, J=12.1,1.6Hz), 3.54 (1H, d, J=12.1Hz), 3.68 (3H, s), 3.38
(3H, s), 2.81 (1H, dd, J=17.3,10.7Hz), 2.62-2.72 (2H, m), 2.42 (1H, dd, J=13.0,4.8Hz),
2.24(1H,m),1.89(1H,m),1.67‐1.82(4H,m),1.57(1H,m),1.51(1H,m),1.20‐1.48(3H,m),
0.97 (1H, m), 0.95 (3H, d, J=7.0Hz)13C NMR(125MHz,CDCl3)δ:175.9(s),150.1(s),140.3
(d),121.4(s),109.5(d),101.8(d),65.1(t),55.8(q),51.7(q),47.0(d),46.1(s),43.0
(d),39.9(s),36.4(d),35.9(t),33.4(t),31.6(d),30.1(t),23.7(t),23.0(t),20.8(t),
17.6 (q) cation ESIMS m/z397 [M+Na]+；HRESIMS m/z397.1989[M+Na]+(calcd for
C22H30O5Na,397.1991).
Embodiment 3:
The preparation of compound 3 and 4
Compound P2 (200mg) is dissolved in 20mL methanol solvate, is added p-methyl benzenesulfonic acid (64mg), in room temperature reaction 8h.
The water 20mL into reaction solution, is extracted with ethyl acetate, and organic phase is washed with saturation NaCl, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure
Obtain pale yellow powder.Compound 3 (114mg, yield 55%) and chemical combination are obtained through silica gel column chromatography (petroleum ether: acetone=8:2)
Object 4 (73mg, yield 35%).
Compound 3: white powder；1H NMR(500MHz,CDCl3) δ: 7.21 (1H, d, J=1.4Hz), 6.17 (1H, d, J
=1.4Hz), 4.76 (1H, br s), 4.04 (1H, dd, J=11.2,2.7Hz), 3.70 (3H, s), 3.54 (1H, d, J=
11.2Hz), 3.35 (3H, s), 2.71 (1H, dd, J=16.1,5.9Hz), 2.62 (1H, m), 2.16-2.34 (3H, m), 2.06
(1H, m), 1.82-1.93 (2H, m), 1.53-1.73 (5H, m), 1.52 (1H, J=11.6,5.9Hz), 1.19-1.36 (2H,
M), 0.96 (3H, d, J=7.1Hz)13C NMR(125MHz,CDCl3)δ:174.9(s),149.1(s),140.5(d),122.3
(s),109.6(d),102.6(d),62.7(t),55.6(q),51.6(q),49.7(s),44.2(d),42.0(d),38.3
(t),37.0(d),36.2(t),36.0(s),31.6(d),30.6(t),23.8(t),22.5(t),21.1(t),17.2(q).
Cation ESIMS m/z397 [M+Na]+；HRESIMS m/z397.1988[M+Na]+(calcd for C22H30O5Na,
397.1991).
Compound 4: white powder；1H NMR(500MHz,CDCl3)δ:7.21(1H,br s),6.17(1H,br s),
5.05 (1H, br s), 4.03 (1H, dd, J=11.6,2.7Hz), 3.81 (1H, dd, J=11.6,1.1Hz), 3.69 (3H, s),
3.53 (3H, s), 2.72 (1H, dd, J=16.3,6.0Hz), 2.63 (1H, m), 2.31 (1H, m), 2.13-2.26 (3H, m),
1.85(1H,m),1.75(1H,m),1.62‐1.74(3H,m),1.49‐1.63(2H,m),1.23‐1.37(3H,m),0.95
(3H, d, J=7.0Hz)13C NMR(125MHz,CDCl3)δ:174.9(s),148.9(s),140.7(d),122.1(s),
109.5(d),101.2(d),66.9(t),57.4(q),51.6(q),49.4(s),47.9(d),41.3(d),38.4(t),
36.3 (d), 35.4 (s), 31.5 (d), 30.0 (t), 29.0 (t), 23.1 (t), 22.5 (t), 21.0 (t), 17.1 (q) just from
Sub- ESIMS m/z397 [M+Na]+；HRESIMS m/z397.1987[M+Na]+(calcd for C22H30O5Na,
397.1991).
Embodiment 4:
The preparation of compound 5
Compound P1 (20mg) is dissolved in 2mL dichloromethane solvent, and PDC (31mg) and 4A molecular sieve (31mg) is added, in
Room temperature reaction is overnight.Reaction solution is filtered with diatomite, and reduced pressure is evaporated, and obtains faint yellow solid.Through silica gel column chromatography (petroleum
Ether: ethyl acetate=8:2) obtain compound 5 (12mg, yield 60%).
Compound 5: colorless needles (methanol)；1H NMR(500MHz,CDCl3)δ:7.21(1H,br s),6.16(1H,br
S), 4.78 (1H, dd, J=12.5,1.7Hz), 4.30 (1H, d J=12.5Hz), 3.74 (1H, m), 3.73 (3H, s), 3.27
(3H, s), 2.64-2.74 (2H, m), 2.31 (1H, br d, J=13.5Hz), 1.87-2.00 (4H, m), 1.55-1.86 (6H,
M), 1.42-1.52 (2H, m), 1.31 (1H, m), 0.97 (3H, d, J=7.1Hz)13C NMR(125MHz,CDCl3)δ:174.0
(s),172.9(s),149.2(s),140.4(d),121.7(s),109.4(d),71.7(t),52.4(q),47.5(s),45.5
(d),44.9(s),43.2(d),36.8(t),36.2(d),34.4(t),31.3(d),29.9(t),26.6(t),23.3(t),
19.5 (t), 18.0 (q) cation ESIMS m/z381 [M+Na]+；HRESIMS m/z381.1677[M+Na]+(calcd for
C21H26O5Na,381.1678).
Embodiment 5:
The preparation of compound 6
Compound P2 (30mg) is dissolved in 3mL dichloromethane solvent, and PDC (90mg) and 4A molecular sieve 90mg is added), in room
Temperature reaction is overnight.Reaction solution is filtered with diatomite, and reduced pressure is evaporated, and obtains faint yellow solid.Through silica gel column chromatography (petroleum ether:
Ethyl acetate=8:2) obtain compound 6 (27mg, yield 90%).
Compound 6: colorless needles (methanol)；1H NMR(500MHz,CDCl3)δ:7.22(1H,br s),6.18(1H,br
S), 4.66 (1H, dd, J=11.9,2.3Hz), 4.24 (1H, d, J=11.9Hz), 3.77 (3H, s), 2.78 (1H, dd, J=
16.2,6.0Hz),2.70(1H,m),2.03‐2.20(4H,m),1.67‐1.92(5H,m),1.53‐1.64(2H,m),1.29‐
1.49 (3H, m), 0.98 (3H, d, J=7.1Hz)13C NMR(125MHz,CDCl3)δ:171.2(s),169.8(s),147.8
(s),141.0(d),122.5(s),109.5(d),73.6(t),55.9(s),52.3(q),46.7(d),40.9(d),38.1
(t),36.0(d),35.4(s),34.8(t),31.2(d),29.1(t),25.2(t),22.5(t),20.0(t),17.2(q).
Cation ESIMS m/z381 [M+Na]+；HRESIMS m/z381.1679[M+Na]+(calcd for C21H26O5Na,
381.1678).
Embodiment 6:
The preparation of compound 7
Compound 1 (40mg) is dissolved in 9mL tetrahydrofuran solvent, and LiAlH is added4(40mg) heats reaction at 75 DEG C
4h.5% sulfuric acid solution of 1mL is added into reaction solution to stir 5 minutes, is extracted with ethyl acetate, extract liquor saturated sodium bicarbonate
Solution washs 3 times, and anhydrous sodium sulfate is dry, and faint yellow solid is concentrated under reduced pressure to obtain.Through silica gel column chromatography (petroleum ether: ethyl acetate
=9:1) obtain compound 7 (33mg, yield 90%).
Compound 7: white powder；1H NMR(500MHz,CDCl3)δ:7.22(1H,br s),6.20(1H,br s),
4.45 (1H, br s), 3.76 (1H, dd, J=11.0,2.3Hz), 3.40, (1H, d, J=10.8Hz), 3.37 (1H, d, J=
), 11.0,1.2Hz 3.29 (1H, d, J=10.8Hz), 3.26 (3H, s), 2.72 (1H, dd, J=15.4,5.1Hz), 2.58
(1H, m), 2.22-2.40 (3H, m), 1.93-2.07 (2H, m), 1.79 (1H, dd, J=11.9,6.2Hz), 1.55-1.73
(3H, m), 1.12-1.36 (7H, m), 0.95 (3H, d, J=7.1Hz)13C NMR(125MHz,CDCl3)δ:149.8(s),
140.3(d),122.4(s),109.8(d),104.7(d),67.4(t),63.8(t),54.5(q),44.7(d),42.5(d),
39.1(s),38.5(t),37.4(s),36.5(d),34.4(t),31.5(t),29.7(t),22.6(t),21.4(t),21.2
(t), 16.9 (q) cation ESIMS m/z369 [M+Na]+；HRESIMS m/z369.2030[M+Na]+(calcd for
C21H30O4Na,369.2042).
Embodiment 7:
The preparation of compound 8
Compound 7 (20mg) is dissolved in 5mL dichloromethane solvent, and acetic anhydride (200 μ L), three second are added under condition of ice bath
Amine (200 μ L), DMAP (3.0mg) are then raised to room temperature reaction 2h naturally.Reaction solution is diluted with water, and water phase is extracted with ethyl acetate
It takes, extract liquor is washed 3 times with saturated sodium chloride solution, and anhydrous sodium sulfate is dry, and faint yellow solid is concentrated under reduced pressure to obtain.Through silicagel column
Chromatography (petroleum ether: ethyl acetate=20:1) obtains compound 8 (18mg, yield 80%).
Compound 8: clear crystal (methanol)；1H NMR(500MHz,CDCl3)δ:7.22(1H,br s),6.20(1H,br
S), 4.44 (1H, br s), 3.71-3.83 (3H, m), 3.41 (1H, m), 3.26 (3H, s), 2.72 (1H, dd, J=15.4,
5.1Hz), 2.58 (1H, m), 2.21-2.39 (3H, m), 2.07 (3H, s), 1.93-2.07 (2H, m), 1.84 (1H, dd, J=
), 13.1,6.1Hz 1.69 (1H, m), 1.39-1.60 (4H, m), 1.11-1.33 (3H, m), 0.96 (3H, d, J=7.1Hz)13C
NMR(125MHz,CDCl3)δ:171.3(s),149.7(s),140.3(d),122.4(s),109.8(d),104.4(d),68.9
(t),63.4(t),54.6(q),45.3(d),42.5(d),39.1(s),38.4(t),36.4(d),36.1(s),34.8(d),
31.5 (d), 29.6 (t), 22.5 (t), 21.6 (t), 21.1 (t), 20.9 (q), 16.9 (q) cation ESIMS m/z411 [M+
Na]+；HRESIMS m/z411.2142[M+Na]+(calcd for C23H32O5Na,411.2147).
Embodiment 8:
The preparation of compound 9
Compound 4 (30mg) is dissolved in 6mL tetrahydrofuran solvent, and LiAlH is added4(30mg) heats reaction at 75 DEG C
4h.5% sulfuric acid solution of 1mL is added into reaction solution to stir 5 minutes, is extracted with ethyl acetate, extract liquor saturated sodium bicarbonate
Solution washs 3 times, and anhydrous sodium sulfate is dry, and faint yellow solid is concentrated under reduced pressure to obtain.Through silica gel column chromatography (petroleum ether: ethyl acetate
=9:1) obtain compound 9 (25mg, yield 93%).
Compound 9: white powder；1H NMR(500MHz,CDCl3)δ:7.22(1H,br s),6.17(1H,br s),
4.65 (1H, br s), 4.02 (1H, dd, J=11.6,2.7Hz), 3.83, (1H, d, J=11.6Hz), 3.70 (1H, d, J=
11.0Hz), 3.48 (3H, s), 3.22 (1H, d, J=11.0Hz), 2.72 (1H, dd, J=16.3,6.0Hz), 2.63 (1H, m),
2.14-2.36 (4H, m), 1.48-1.76 (6H, m), 1.17-1.41 (5H, m), 0.95 (3H, d, J=7.1Hz)13C NMR
(125MHz,CDCl3)δ:149.1(s),140.1(d),122.1(s),109.6(d),105.0(d),68.6(t),67.3(t),
56.7(q),47.8(d),41.3(d),40.0(s),39.1(t),36.2(d),35.9(s),31.6(d),30.2(t),29.0
(t), 22.5 (t), 21.2 (t), 20.5 (t), 17.2 (q) cation ESIMS m/z369 [M+Na]+；HRESIMS m/
z369.2030[M+Na]+(calcd for C21H30O4Na,369.2042).
Embodiment 9:
The preparation of compound 10
Compound 9 (10mg) is dissolved in 5mL dichloromethane solvent, and acetic anhydride (100 μ L), three second are added under condition of ice bath
Amine (100 μ L), DMAP (1.5mg) are then raised to room temperature reaction 2h naturally.Reaction solution is diluted with water, and water phase is extracted with ethyl acetate
It takes, extract liquor is washed 3 times with saturated sodium chloride solution, and anhydrous sodium sulfate is dry, and faint yellow solid is concentrated under reduced pressure to obtain.Through silicagel column
Chromatography (petroleum ether: ethyl acetate=20:1) obtains compound 10 (9mg, yield 81%).
Compound 10: white powder；1H NMR(500MHz,CDCl3)δ:7.21(1H,br s),6.17(1H,br s),
4.52 (1H, br s), 4.02 (1H, dd, J=11.5,2.6Hz), 3.92, (1H, d, J=11.3Hz), 3.89 (1H, d, J=
11.3Hz), 3.82 (1H, d, J=11.5Hz), 3.41 (3H, s), 2.72 (1H, dd, J=16.3,6.0Hz), 2.64 (1H, m),
2.34 (1H, m), 2.14-2.26 (2H, m), 2.09 (3H, s), 1.95 (1H, dd, J=13.3,5.6Hz), 1.46-1.76 (6H,
M), 1.17-1.44 (4H, m), 0.96 (3H, d, J=7.1Hz)13C NMR(125MHz,CDCl3)δ:171.3(s),149.1
(s),140.6(d),122.1(s),109.6(d),102.8(d),67.6(t),67.3(t),57.0(q),46.0(d),41.3
(d),39.5(s),38.8(t),36.4(d),35.9(s),31.6(d),30.3(t),29.4(t),22.5(t),21.1(t),
21.0 (q), 20.7 (t), 17.2 (q) cation ESIMS m/z411 [M+Na]+；HRESIMS m/z411.2144[M+Na]+
(calcd for C23H32O5Na,411.2147).
Embodiment 10:
The preparation of compound 11
Compound P2 (30mg) is dissolved in 6mL tetrahydrofuran solvent, and LiAlH is added4(30mg) heats reaction at 75 DEG C
4h.5% sulfuric acid solution of 1mL is added into reaction solution to stir 5 minutes, is extracted with ethyl acetate, extract liquor saturated sodium bicarbonate
Solution washs 3 times, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure.Sample after concentration continues to be dissolved in 5mL dichloromethane solvent, adds
Enter IBX (300mg) in room temperature reaction 12h.Appropriate saturated sodium bicarbonate solution is added, is extracted with ethyl acetate 3 times, aqueous sodium persulfate
It is dry, faint yellow solid is concentrated under reduced pressure to obtain.Through silica gel column chromatography (petroleum ether: ethyl acetate=8:2) obtain compound 11 (9mg,
Yield 34%).
Compound 11: white powder；1H NMR(500MHz,CDCl3)δ:10.2(1H,s),7.22(1H,br s),6.18
(1H, br s), 4.66 (1H, dd, J=12.0,2.2Hz), 4.28, (1H, d, J=12.0Hz), 2.78 (1H, dd, J=16.1,
6.0Hz),2.69(1H,m),2.16(1H,m),1.99‐2.12(2H,m),1.81‐1.94(3H,m),1.61‐1.79(4H,m),
1.11 (1H, m), 1.21-1.38 (3H, m), 0.95 (3H, d, J=7.1Hz)13C NMR(125MHz,CDCl3)δ:202.1
(d),172.0(s),147.4(s),141.0(d),122.6(s),109.5(d),73.9(t),56.8(s),44.6(d),40.4
(d),37.9(t),36.3(t),35.5(s),33.7(t),31.3(d),28.9(t),24.3(t),22.5(t),21.2(t),
20.0 (t), 17.3 (q) cation ESIMS m/z351 [M+Na]+；HRESIMS m/z351.1575[M+Na]+(calcd for
C20H24O4Na,351.1572).
Embodiment 11:
The preparation of compound 12
Compound 9 (10mg) is dissolved in 2mL dichloromethane solvent, and IBX (100mg) is added in room temperature reaction 12h.It is added suitable
Saturated sodium bicarbonate solution is measured, is extracted with ethyl acetate 3 times, aqueous sodium persulfate is dry, and faint yellow solid is concentrated under reduced pressure to obtain.Through silica gel
Column chromatography (petroleum ether: ethyl acetate=8:2) obtains compound 12 (9mg, yield 90%).
Compound 12: white powder；1H NMR(500MHz,CDCl3)δ:9.5(1H,s),7.21(1H,br s),6.17
(1H, br s), 5.05 (1H, br s), 4.08 (1H, dd, J=11.7,2.7Hz), 3.84 (1H, d, J=11.7Hz), 3.52
(3H, s), 2.73 (1H, dd, J=16.3,6.0Hz), 2.63 (1H, m), 2.07-2.36 (4H, m), 1.46-1.83 (8H, m),
1.22-1.39 (2H, m), 0.95 (3H, d, J=7.1Hz)13C NMR(125MHz,CDCl3)δ:205.1(d),148.7(s),
140.7(d),122.1(s),109.6(d),100.5(d),67.2(t),57.2(q),51.7(s),45.9(d),41.3(d),
38.3(t),36.4(d),35.2(s),31.5(d),29.9(t),27.5(t),22.5(t),22.3(t),20.7(t),17.1
(q) cation ESIMS m/z367 [M+Na]+；HRESIMS m/z367.1886[M+Na]+(calcd for C21H28O4Na,
367.1885).
Embodiment 12:
The preparation of compound 13
Compound P1 (20mg) is dissolved in 6mL tetrahydrofuran solvent, and KOH (10mg) heating reaction 3h at 75 DEG C is added.
It is cooled to room temperature, 1mL1N hydrochloric acid solution is added into reaction solution and stirs 5 minutes, is extracted with ethyl acetate, extract liquor saturated carbon
Sour hydrogen sodium solution washs 3 times, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure.Sample after concentration continues to be dissolved in 5mL dichloromethane solvent
In, PDC (30mg) is added in room temperature reaction 12h.Appropriate saturated sodium bicarbonate solution is added, is extracted with ethyl acetate 3 times, water sulphur
Sour sodium is dry, and faint yellow solid is concentrated under reduced pressure to obtain.Compound 13 is obtained through silica gel column chromatography (petroleum ether: ethyl acetate=8:2)
(12mg, yield 73%).
Compound 13: white powder；1H NMR(500MHz,CDCl3)δ:7.22(1H,br s),6.18(1H,br s),
4.58 (1H, dd, J=11.9,2.1Hz), 4.23, (1H, d, J=11.9Hz), 2.58-2.81 (2H, m), 1.99-2.35 (4H,
M), 1.57-1.91 (7H, m), 1.17-1.54 (4H, m), 1.00 (3H, d, J=7.1Hz)13C NMR(125MHz,CDCl3)δ:
173.8(s),148.1(s),140.9(d),122.6(s),109.6(d),73.8(t),43.8(d),43.7(d),40.5(d),
38.5 (t), 36.5 (d), 31.4 (d), 30.3 (t), 29.4 (t), 22.4 (t), 20.4 (t), 17.4 (q) cation ESIMS
m/z323[M+Na]+.
Embodiment 13:
Inhibiting effect of the compound 1-13 to gluconeogenesis:
(1) experimental method:
A, Rat Fast for 24 hours afterwards after the chloraldurate intraperitoneal injection of anesthesia of 500mg/kg, open rapidly by whole body alcohol disinfecting
Abdomen, portal catheterization are fixed, and are usedPreceding perfusate with 10~15ml/min perfusion, while cutting inferior caval vein, about
10mins。
B, the rear perfusion solution containing clostridiopetidase A is changed with 5~7ml/min perfusion, and perfusion to Glisson's capsule undertissue is split in turtleback
Gap or portal vein stop when rupturing, time about 15~20min.
C, after perfusion, complete liver is separated, is placed in the culture dish containing identical training liquid through the cleaning of MEM culture solution,
Glisson's capsule is torn off with tweezers, after gently blowing and beating dispersion with dropper, filtrate is drawn onto 50ml centrifuge tube by 100 mesh net filtrations, from
The heart 500rpm, 3min abandon supernatant.
D, Percoll separates cell, is centrifuged 500rpm, 5min.Suck supernatant and dead cell.10%FBSMEM training is added
Nutrient solution (insulin containing 10nM and 10nM DEX) suspension cell carries out cytoactive detection through 0.4% trypan blue and counts, presses
1.3 × 105/well cell inoculation is placed in the 48-well culture plate for being covered with gelatin5%CO2It is trained in incubator
It supports.
E, Rat Primary Hepatocytes culture 4h after adherent, changes to the compound containing various concentration, 0.1%DMSO (solvent
Control) or 500 μM of Metformin (positive control) sugar-free DMEM culture solution, pre-process 1.5h after, change containing work be free of
Have the compound of gluconeogenesis substrate (20mM sodium lactate, 2mM Sodium Pyruvate) and various concentration, 0.1%DMSO (solvent control) or
The sugar-free DMEM solution of 500 μM of Metformin (positive control).After being incubated for 4h, training liquid is collected, detector glucose is dense
Degree.Meanwhile 0.5M NaOH lytic cell being added after with PBS washing cell 3 times, measurement protein concentration simultaneously corrects Portugal through protein concentration
The amount of glucose produced by unit cell number is acquired after grape sugar reading.
(2) experimental result:
The experimental results showed that compound 1-13 to hepatic gluconeogenic have significantly inhibit effect, have treat diabetes B and
The potentiality of other metabolic diseases.
Influence of 1. the compounds of this invention of table to hepatic gluconeogenesis
aGluconeogenesis value is 0.61 at 500 μM of positive control melbine
Embodiment 14:
The preparation of tablet:
Above compound of the invention is first made by the method for embodiment 1-12, is 1:5-1 by itself and excipient weight ratio:
Excipient, pelletizing press sheet is added in 10 ratio.
Embodiment 15:
The preparation of oral liquid formulations:
Above compound of the invention is first made by the method for embodiment 1-12, and utilizes organic acid (tartaric acid, lemon
Acid, formic acid, ethanedioic acid etc.) or inorganic acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.) made of salt, routinely oral solution preparation method is made oral
Liquid.
Embodiment 16:
The preparation of capsule, granule or electuary:
Above compound of the invention is first made by the method for embodiment 1-12, by its with excipient weight than for 5:1's
Excipient is added in ratio, and capsule or granule or electuary is made.
Claims (8)
1. furans card mountain alkane forskolin shown in formula (I),
In formula, X is selected from O or NH；
R1Selected from hydrogen, methyl, aldehyde radical, carboxyl, methylol, methylene halogen, C1-10Alkoxymethylene, C2-10Acyloxy methylene
Base ,-COOR, isocyanate group,-CH2NH2、
Wherein halogen is fluorine, chlorine, bromine；
R is C2-10Alkyl；
When R '=H, R "=C1-10Alkyl or C2-10Acyl group, R '=C1-10When alkyl, R "=R '；
R2、R3It is respectively selected from H, carbonyl, C1-10Alkoxy.
2. furans card mountain alkane forskolin shown in formula (I) as described in claim 1 is following structure formula (II) and formula
(III) card mountain alkane forskolin shown in,
In formula, X is selected from O or NH；
R1Selected from hydrogen, methyl, aldehyde radical, carboxyl, methylol, methylene halogen, C1-10Alkoxymethylene, C2-10Acyloxy methylene
Base ,-COOR, isocyanate group,-CH2NH2、
Wherein halogen is fluorine, chlorine, bromine；
R is C2-10Alkyl；
When R '=H, R "=C1-10Alkyl or C2-10Acyl group, R '=C1-10When alkyl, R "=R '.
3. furans card mountain alkane forskolin shown in formula (I) as described in claim 1 is following structural formula (IV) and formula
(V) card mountain alkane forskolin shown in,
In formula, R1Selected from hydrogen, methyl, aldehyde radical, carboxyl, methylol, methylene halogen, C1-10Alkoxymethylene, C2-10Acyloxy
Methylene ,-COOR, isocyanate group,-CH2NH2、
Wherein halogen is fluorine, chlorine, bromine；
R is C2-10Alkyl,；
When R '=H, R "=C1-10Alkyl or C2-10Acyl group, R '=C1-10When alkyl, R "=R '.
4. the furans card mountain alkane forskolin as described in claims 1 or 2 or 3 is following compound 7-13:
5. the pharmaceutical composition for treating or preventing diabetes B, wherein claims 1 or 2 containing therapeutically effective amount or 3
Or furans card mountain alkane forskolin and pharmaceutically acceptable carrier described in 4.
6. pharmaceutical composition described in furans card mountain alkane forskolin or claim 5 shown in claims 1 or 2 or 3 or 4
Application of the object in the drug that preparation treats or prevents diabetes B.
7. furans card mountain alkane diterpene phanginin E and its derivative shown in formula (VI) treat or prevent 2 type glycosurias in preparation
Application in the drug of disease,
Wherein, R1And R2Selected from hydrogen, hydroxyl, methoxyl group or carbonyl, work as R1For carbonyl, R2When for hydrogen atom, compound is
phanginin E；Work as R2For carbonyl, R1When for hydrogen atom, compound is 19-deoxo-20-oxophanginin E.
8. the preparation method of furans card as claimed in claim 4 mountain alkane forskolin, it is characterised in that this method includes following
Step:
(1) preparation of compound 7:
Bush seed 10kg is extracted three times with 95% ethyl alcohol in soaking at room temperature, 48 hours every time, combined extract decompression after crushing
It is concentrated to give crude extract, crude extract is dispersed in water, is extracted four times with isometric ethyl acetate, extract liquor, second is concentrated under reduced pressure
Through silica gel column chromatography, column chromatographs and is recrystallized to give compound P1 and P2 to acetoacetic ester extract repeatedly；
Compound P1 is dissolved in 10mL methanol solvate, and p-methyl benzenesulfonic acid is added, and in room temperature reaction 8h, water is added into reaction solution
15mL is extracted with ethyl acetate, and organic phase is washed with saturation NaCl, and anhydrous sodium sulfate is dry, and pale yellow powder is concentrated under reduced pressure to obtain,
Through silica gel column chromatography petroleum ether: acetone=8:2 obtains compound 1 and compound 2；
Compound 1 is dissolved in 9mL tetrahydrofuran solvent, and LiAlH is added440mg heats reaction 4h at 75 DEG C, adds into reaction solution
Enter 5% sulfuric acid solution of 1mL to stir 5 minutes, be extracted with ethyl acetate, extract liquor washs 3 times with saturated sodium bicarbonate solution, nothing
Aqueous sodium persulfate is dry, faint yellow solid is concentrated under reduced pressure to obtain, through silica gel column chromatography petroleum ether: ethyl acetate=9:1 obtains compound
7；
(2) preparation of compound 8:
Compound 7 is dissolved in 5mL dichloromethane solvent, and 200 μ L of acetic anhydride, 200 μ L of triethylamine, DMAP are added under condition of ice bath
3.0mg is then raised to room temperature reaction 2h naturally, and reaction solution is diluted with water, and water phase is extracted with ethyl acetate, extract liquor saturation chlorine
Change sodium solution to wash 3 times, anhydrous sodium sulfate is dry, faint yellow solid is concentrated under reduced pressure to obtain, through silica gel column chromatography petroleum ether: acetic acid second
Ester=20:1 obtains compound 8；
(3) preparation of compound 9:
Compound P2 is dissolved in 20mL methanol solvate, and p-methyl benzenesulfonic acid 64mg is added, and in room temperature reaction 8h, water is added into reaction solution
20mL is extracted with ethyl acetate, and organic phase is washed with saturation NaCl, and anhydrous sodium sulfate is dry, and pale yellow powder is concentrated under reduced pressure to obtain,
Through silica gel column chromatography petroleum ether: acetone=8:2 obtains compound 3 and compound 4；
Compound 4 is dissolved in 6mL tetrahydrofuran solvent, and LiAlH is added430mg heats reaction 4h at 75 DEG C, into reaction solution
5% sulfuric acid solution of 1mL is added to stir 5 minutes, is extracted with ethyl acetate, extract liquor is washed 3 times with saturated sodium bicarbonate solution,
Anhydrous sodium sulfate is dry, faint yellow solid is concentrated under reduced pressure to obtain, through silica gel column chromatography petroleum ether: ethyl acetate=9:1 obtains chemical combination
Object 9；
(4) preparation of compound 10:
Compound 9 is dissolved in 5mL dichloromethane solvent, under condition of ice bath be added 100 μ L of acetic anhydride, 100 μ L of triethylamine,
DMAP 1.5mg is then raised to room temperature reaction 2h naturally, and reaction solution is diluted with water, and water phase is extracted with ethyl acetate, and extract liquor is used
Saturated sodium chloride solution is washed 3 times, and anhydrous sodium sulfate is dry, and faint yellow solid is concentrated under reduced pressure to obtain, through silica gel column chromatography petroleum ether:
Ethyl acetate=20:1 obtains compound 10；
(5) preparation of compound 11:
Compound P2 is dissolved in 6mL tetrahydrofuran solvent, and LiAlH is added430mg heats reaction 4h at 75 DEG C, into reaction solution
5% sulfuric acid solution of 1mL is added to stir 5 minutes, is extracted with ethyl acetate, extract liquor is washed 3 times with saturated sodium bicarbonate solution,
Anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and the sample after concentration continues to be dissolved in 5mL dichloromethane solvent, be added IBX 300mg in
12h is reacted at room temperature, appropriate saturated sodium bicarbonate solution is added, is extracted with ethyl acetate 3 times, anhydrous sodium sulfate is dry, depressurizes dense
Contract to obtain faint yellow solid, through silica gel column chromatography petroleum ether: ethyl acetate=8:2 obtains compound 11；
(6) preparation of compound 12:
Compound 9 is dissolved in 2mL dichloromethane solvent, and IBX 100mg is added in room temperature reaction 12h, appropriate unsaturated carbonate is added
Hydrogen sodium solution is extracted with ethyl acetate 3 times, and anhydrous sodium sulfate is dry, faint yellow solid is concentrated under reduced pressure to obtain, through silica gel column chromatography stone
Oily ether: ethyl acetate=8:2 obtains compound 12；
(7) preparation of compound 13:
Compound P1 20mg is dissolved in 6mL tetrahydrofuran solvent, and KOH 10mg is added and heats reaction 3h at 75 DEG C, is cooled to
Room temperature is added 1mL 1N hydrochloric acid solution into reaction solution and stirs 5 minutes, is extracted with ethyl acetate, extract liquor unsaturated carbonate hydrogen
Sodium solution washs 3 times, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and the sample after concentration continues to be dissolved in 5mL dichloromethane solvent,
PDC 30mg is added in room temperature reaction 12h, appropriate saturated sodium bicarbonate solution is added, is extracted with ethyl acetate 3 times, anhydrous slufuric acid
Sodium is dry, faint yellow solid is concentrated under reduced pressure to obtain, through silica gel column chromatography petroleum ether: ethyl acetate=8:2 obtains compound 13.
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| Phanginin A–K, diterpenoids from the seeds of Caesalpinia sappan Linn.;Orapun Yodsaoue,et al.,;《Phytochemistry》;20081231;第69卷;第1242-1249页 * |
| Three new cassane diterpenes from the seeds of Caesalpinia sappan;Guo-Xu Ma，et al.,;《Phytochemistry Letters》;20140402;第8卷;第141-144页 * |
| Two new cassane diterpenoids from the seeds of Caesalpinia sappan Linn.;ZHANG Jing-Yu,et al.,;《Chinese Journal of Natural Medicines》;20120520;第10卷(第3期);第218-221页 * |
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