CN106748667A - A kind of derivative of natural products selaginpulvilin and its preparation method and application - Google Patents
A kind of derivative of natural products selaginpulvilin and its preparation method and application Download PDFInfo
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- C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
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Abstract
The invention belongs to medicine and the technical field of chemical industry, a kind of derivative of natural products selaginpulvilin is disclosed, present invention simultaneously provides the preparation method of said derivative and as the application prepared on anti-inflammatory drug.Shown in the structure such as formula (I) or formula (II) of the natural products selaginpulvilin derivatives being related in the present invention.Wherein, R1It is alkyl, aldehyde radical, carboxyl, alcohol radical, hydroxyl, acyl group or hydrogen；R2It is hydrogen or hydroxyl；R3It is alkoxy, acyl group or hydroxyl；R4It is halogen, fragrant acetenyl, phenyl or substituted-phenyl, aromatic ethylene base；R5It is hydrogen, hydroxyl, phenyl or substituted-phenyl；R6It is hydrogen, phenyl or substituted-phenyl；Substitution base is selected from alkoxy, acyl group or hydroxyl；The derivative of above-mentioned natural products selaginpulvilin has significant inhibitory action to phosphodiesterase IN, there is wide application space on anti-inflammatory drug is prepared.
Description
Technical field
The present invention relates to medicine and chemical field, more particularly, to a kind of spreading out for natural products selaginpulvilin
Biology and its preparation method and application.
Background technology
Cyclic nucleotide phosphodiesterase (Cyclic nucleotide phosphodiesterases, PDEs) is a class weight
The super enzyme family wanted, by CAMP (Cyclic Adenosine monophosphate, Camp) and cGMP
Hydrolysis, effectively controls intracellular cAMP and cyclic guanosine monophosphate (cyclic guanosine monophosphate, cGMP) dense
Degree, so as to adjust the biochemical action that internal second messenger is conducted.PDEs is widely distributed in mammalian tissues, its diversity
Cause different PDE enzymes has specific distribution in cell and subcellsular level, and optionally adjustable various kinds of cell function, is good
Good drug design and therapy target.
Phosphodiesterase IN (PDE4) hydrolyzes the PDE families enzyme of cAMP as specific catalytic, is mainly distributed in human body
In in inflammatory cell.In inflammatory reaction, cAMP plays the down regulation of key to physiology courses such as the releases of cell factor,
Therefore will be helpful to injury of the reaction to body that reduce inflammation by suppressing PDE4 raising intracellular cAMP concentrations.At present, PDE4
Inhibitor has been developed that into the medicine of anti-inflammatory, such as roflumilast (Roflumilast), is clinically mainly used in treating lung
Inflammation, in particular in the treatment of asthma and chronic obstructive pulmonary disease.But taking such medicine can cause diarrhoea, nausea etc.
Adverse reaction, therefore how to overcome the adverse reaction that these PDE4 inhibitor are present, study new specific inhibitor just into
One of focus for research.Natural products is to find one of important sources with Novel PDE 4 inhibitors, for exploitation new
For curative effect is strong, Small side effects PDE4 inhibitor have great importance.
Early stage we 6 are obtained from the Chinese medicine Selaginella pulvinata (Selaginella pulvinata) there is notable PDE4 suppressions
Make 9, the 9- diphenyl -1- phenylacetylene new molecule of the skeleton of -9H- fluorenes of activity, its IC50Value is better than sun between 0.011-0.26 μM
Property comparison medicine rolipram (IC50=0.54 μM).The discovery of the new skeleton active natural compounds of one class, might mean that one newly
Medicine appearance.Therefore, it is of the invention on the basis of early-stage Study, first to 9,9- diphenyl -1- phenylacetylene -9H- fluorenes
New molecule of the skeleton has carried out fully synthetic, and a series of derivatives of acquisition have significant PDE4 inhibitory action.
The content of the invention
The invention aims to provide a kind of new natural products selaginpulvilin's with anti-inflammatory activity
Derivative.
Preparation side another object of the present invention is to provide the derivative of above-mentioned natural products selaginpulvilin
Method.
Derivative it is still another object of the present invention to provide above-mentioned natural products selaginpulvilin is anti-as preparing
Application in scorching medicine.
The invention provides a kind of preparation method of the derivative of natural products selaginpulvilin, the natural product
Shown in the structural formula of the derivative of thing selaginpulvilin such as formula (I) or formula (II),
Wherein, R1It is alkyl, aldehyde radical, carboxyl, alcohol radical, hydroxyl, acyl group or hydrogen；R2It is hydrogen or hydroxyl；R3It is alkoxy, acyl
Base or hydroxyl；R4It is halogen, fragrant acetenyl, phenyl or substituted-phenyl, aromatic ethylene base；R5It is hydrogen, hydroxyl, phenyl or substituted-phenyl；
R6It is hydrogen, phenyl or substituted-phenyl；Substitution base is selected from alkoxy, acyl group or hydroxyl；
The preparation method specifically includes following steps：
S1. the bromobenzoic acid class compound shown in formula (III) and iodoacetic acid react, and obtain structural formula as shown in formula (IV)
Compound；
S2. the compound by step S1 gained as shown in structure formula (IV) is anti-with iodomethane, phenylboronic acid compound successively
Compound of the structural formula as shown in formula (V) should be obtained；Wherein, X is bromine or hydrogen；
S3. compound of the structural formula for step S2 being obtained as shown in formula (V) is reacted with methanesulfonic acid, obtains structural formula
Compound as shown in formula (VI)；Wherein, X is bromine or hydrogen；
S4. when X is bromine, compound of the structural formula as shown in formula (VI) and fragrant acetylene compound reaction are tied
Compound of the structure formula as shown in formula (VII)；
S5. compound of the structural formula for step S4 being obtained as shown in formula (VII) and RMgBr magnesium bromide class compound
After being reacted, compound of the structural formula as shown in formula (VIII) is obtained；
S6. compound of the structural formula for step S5 being obtained as shown in formula (VIII) is reacted with methyl phenyl ethers anisole class compound
Afterwards, compound of the structural formula as shown in formula (I) is obtained；
S7. compound of the structural formula for step S6 being obtained as shown in formula (I) by after de- alkyl, bromo acylation reaction,
Reacted with sodium dihydrogen phosphate and sodium chlorite again, finally reacted with silver carbonate, obtain compound of the structural formula as shown in formula (II).
Preferably, R1It is hydrogen, carboxyl, aldehyde radical, hydroxyl, methylol, C1~5Alkyl, dimethoxymethane base, acetyl group, first
Epoxide or ethyoxyl；R2It is hydrogen or hydroxyl；R3It is methoxyl group, hydroxyl, acetyl group；R4For halogen, to Methoxy-phenylacetylene base, right
Hydroxyl phenylacetylene base, to acetylbenzene acetenyl, 4- hydroxy phenyls, (Z) -1- bromo- 2- (p-hydroxybenzene) vinyl,；R5For
Hydrogen, hydroxyl, 4- hydroxy phenyls, p-methoxyphenyl or to acetylphenyl；R6It is hydrogen, 4- hydroxy phenyls, p-methoxyphenyl
Or to acetylphenyl.
Preferably, reaction temperature is 80~120 DEG C in S1 steps, and the reaction time is 20~30h.
Preferably, reaction temperature is 60~70 DEG C in S3 steps, and the reaction time is 5~7h.
First passage of the present invention is artificial synthesized to obtain said derivative, is compared to and is extracted from plant, more accelerates
It is prompt efficient.
The present invention also provides a kind of derivative of natural products selaginpulvilin, the natural products
Shown in the structural formula of the derivative of selaginpulvilin such as formula (I) or formula (II),
Wherein, R1It is alkyl, aldehyde radical, carboxyl, alcohol radical, hydroxyl, acyl group or hydrogen；R2It is hydrogen or hydroxyl；R3It is alkoxy, acyl
Base or hydroxyl；R4It is halogen, fragrant acetenyl, phenyl or substituted-phenyl, aromatic ethylene base；R5It is hydrogen, hydroxyl, phenyl or substituted-phenyl；
R6It is hydrogen, phenyl or substituted-phenyl；Substitution base is selected from alkoxy, acyl group or hydroxyl.
Preferably, R1It is hydrogen, carboxyl, aldehyde radical, hydroxyl, methylol, C1~5Alkyl, dimethoxymethane base, acetyl group, first
Epoxide or ethyoxyl；R2It is hydrogen or hydroxyl；R3It is methoxyl group, hydroxyl, acetyl group；R4For halogen, to Methoxy-phenylacetylene base, right
Hydroxyl phenylacetylene base, to acetylbenzene acetenyl, 4- hydroxy phenyls, (Z) -1- bromo- 2- (p-hydroxybenzene) vinyl,；R5For
Hydrogen, hydroxyl, 4- hydroxy phenyls, p-methoxyphenyl or to acetylphenyl；R6It is hydrogen, 4- hydroxy phenyls, p-methoxyphenyl
Or to acetylphenyl.
It is highly preferred that working as R2During for hydrogen, R1It is asynchronously hydrogen, methyl, aldehyde radical or methylol；
Work as R6During for 4- hydroxy phenyls, R1It is asynchronously methyl or methylol.
The more specifically selaginpulvilin derivatives that the present invention is provided are as shown in Figure 1：
More specifically, there is provided a kind of application of natural products selaginpulvilin derivatives.It is natural that the present invention is provided
Product selaginpulvilin derivatives are a class PDE4 type inhibitor, strong, Small side effects for exploitation curative effect of new generation
PDE4 inhibitor has great importance.
For a better understanding of the present invention, further explaination is made to the present invention program association reaction formula below, it is listed
Reaction equation is only theory deduction gained, its limitation that cannot function as the scope of the present invention.By taking the synthesis of HC-1-HC-6 as an example,
Specific building-up process of the invention, it is as follows：
Comprise the following steps that：
The bromo- 3- methyl-benzoic acids (compound 1) of 2- are dissolved in DMF (DMF), add equivalent
Iodine, iodobenzene diacetate, the palladium of catalytic amount, nitrogen protection lower 100 DEG C of stirrings 24h cross post purifying and obtain compound after extraction
2, yield 86%.Compound 2 dissolves in acetone, adds excessive iodomethane and potassium carbonate, 60 DEG C of degree to be heated to reflux 3h, cools down
It is concentrated under reduced pressure after to room temperature, adds the 4- methoxyphenylboronic acids of equivalent, excessive potassium carbonate, four (triphenylphosphines) of catalytic amount
Palladium, DMF and water are solvent, and lower 100 DEG C of nitrogen protection is stirred overnight and obtains compound 3, yield 67%.Compound 3 is in methanesulfonic acid
Middle backflow 6h, is obtained by extraction compound 4, yield 92%.The equivalent 4- Methoxy-phenylacetylenes of compound 4,1.2, and catalytic amount four
(triphenylphosphine) palladium, triphenylphosphine, cuprous iodide, add DMF and Et under nitrogen protection3N, 120 DEG C are stirred overnight, and are cooled to
After room temperature, ethyl acetate is extracted and crosses post purifying and obtains compound 5, yield 85%.Compound 5 is dissolved in anhydrous tetrahydro furan
(THF), it is placed in ice bath, nitrogen protection is lower to add 4- methoxyphenyl-magnesium bromides, is stirred overnight after being gradually restored to room temperature, extracts
Post purifying is crossed after taking and obtains compound 6, yield 88%.Compound 6 is dissolved in dichloromethane (DCM), add excessive methyl phenyl ethers anisole and
The methanesulfonic acid of equivalent, reacts 1h at room temperature, and compound HC-11, yield 63% are obtained after extraction.Compound HC-11 is dissolved in anhydrous
DCM, is placed in ice bath, and excessive BBr is added dropwise under nitrogen protection3, 2h is stirred for after being gradually restored to room temperature, mistake after extraction
Post purifying obtains HC-3, yield 65%.
HC-3 is dissolved in pyridine, adds excess acetic anhydride, is stirred overnight at room temperature, and compound HC-12 is obtained after extraction, is produced
Rate 68%.HC-12 is dissolved in anhydrous CCl4In, nitrogen protection is lower to add NBS, AIBN, 80 DEG C of excessive backflow 12h, filtering, filtrate
Excessive potassium hydroxide, Isosorbide-5-Nitrae-dioxane/water (1 are added after pressurization concentration：1) it is solvent, 1h is reacted at room temperature, obtains HC-1
And HC-2 (30%) (59%).HC-2 is dissolved in dimethyl sulfoxide (DMSO) (DMSO), adds excessive sodium chlorite and sodium dihydrogen phosphate, room
It is stirred overnight under temperature, HC-6, yield 81% is obtained after extraction.HC-6 flows back in concentrated hydrochloric acid, obtains HC-4 (61%).HC-6 with
The silver carbonate of catalytic amount is dissolved in DMSO, and 120 DEG C of reactions overnight, after extraction obtain HC-5 (85%).
Compared with prior art, the present invention has following beneficial effect：
The compound that the present invention is provided has significant inhibitory action to PDE4, has in terms of new anti-inflammatory drug is prepared
There is good application prospect.The preparation method of the derivative of natural products selaginpulvilin disclosed in this invention, headed by
It is secondary fully synthetic, such compound phase ratio, more quickness and high efficiency is extracted from plant with existing.
Brief description of the drawings
The derivant structure formula figure of the natural products selaginpulvilin that Fig. 1 is provided for the present invention.
Specific embodiment
Below in conjunction with specific embodiments and the drawings, the invention will be further described, but specific embodiment is not to the present invention
It is limited in any way.
Embodiment 1：
The bromo- 3- methyl benzoic acids (21.3mmol) of 2-, palladium (0.24g, 1.06mmol), iodobenzene diacetate (6.86g,
21.3mmol) it is placed in 250mL round-bottomed flasks with iodine (5.42g, 21.3mmol).Add DMF (50mL) dissolvings, 100 DEG C of reactions
24-36h.500mL ethyl acetate is added after being cooled to room temperature, with three DMF that go out of 0.5N salt acid elution.Organic layer decompression is dense
Contracting, crosses post purifying (petroleum ether/dichloromethane) and obtains compound 2.
Embodiment 2：
Compound 2 (20.0mmol) is dissolved in acetone (50.0mL), K is successively added at room temperature2CO3(5.52g,
40.0mmol) with MeI (1.9mL, 30.0mmol), flow back 3h.Add water quenching to go out after the completion of reaction, be extracted with ethyl acetate three
It is secondary.Merge organic layer and be concentrated under reduced pressure, obtain esterification products.
Above-mentioned esterification products (15.4mmol), 4- methoxyphenylboronic acids (2.34g, 15.4mmol), Pd (PPh3)4(0.89g,
0.77mmo), and K2CO3(6.37g, 46.1mmol) is placed in two-neck bottle, and nitrogen protection is lower to add DMF (50mL) and H2O
(8mL).It is stirred overnight at 100 DEG C, saturated aqueous ammonium chloride is added after being cooled to room temperature, is extracted with ethyl acetate three times.Close
And organic layer, cross post purifying (petroleum ether/dichloromethane) after being concentrated under reduced pressure and obtain compound 3.
Embodiment 3：
Compound 3 (13.3mmol) is dissolved in MeSO3H(10mL).It is stirred overnight at 65 DEG C, water is added after the completion of reaction
(200mL) is quenched, and is extracted with ethyl acetate three times.Merge organic layer, be concentrated under reduced pressure to give compound 4.
Embodiment 4：
By compound 4 (3.85mmol), 4- Methoxy-phenylacetylenes (0.55mL, 4.24mmol), Pd (PPh3)4(220mg,
0.19mmol),CuI(37mg,0.19mmol),PPh3(102mg,0.39mmol),DMF(5mL),Et3N (5mL) is placed in two-neck bottle
In, nitrogen protection lower 120 DEG C of backflows 14-24h is cooled to room temperature after the completion of reaction, add water dilution, is extracted with ethyl acetate three
It is secondary, merge organic layer, normal phase silicagel column purifying (petroleum ether/dichloromethane), obtains compound 5 after being concentrated under reduced pressure.
Embodiment 5：
It is dissolved in anhydrous THF (10mL) under compound 5 (6.75mmol) nitrogen is protected, 4- first is added dropwise under ice bath
Phenyl magnesium bromide (1.0M, 13.5mL, 13.5mmol), continues to stir 6-8h in ice bath, until having reacted after dripping
(detected by TLC) entirely.Add water quenching to go out, be extracted with ethyl acetate three times, merge organic layer, normal phase silicagel column after being concentrated under reduced pressure
Purifying (petroleum ether/dichloromethane), obtains compound HC-21.
HC-21：1H NMR(400MHz,CDCl3) δ 7.46 (d, J=8.1Hz, 1H), 7.41 (d, J=7.8Hz, 1H),
7.35 (d, J=8.7Hz, 2H), 7.21 (d, J=7.8Hz, 1H), 7.15 (d, J=8.6Hz, 2H), 6.83 (dd, J=8.1,
2.2Hz,1H),6.82-6.78(m,5H),3.77(s,3H),3.72(s,6H),2.45(s,3H).13C NMR(100MHz,
CDCl3)δ160.2,159.8,158.7,151.9,150.6,138.8,138.4,135.6,132.9,131.2,130.2,
126.6,120.8,119.4,118.7,115.0,114.8,114.0,113.6,110.0,99.5,83.8,55.5,55.4,
55.3,20.4；ESIMS m/z 463.2[M+H]+.
Embodiment 6：
Compound HC-21 (5.52mmol) and methyl phenyl ethers anisole (0.72mL, 6.62mmol) are dissolved in DCM (10mL), are stirred
Lower addition MeSO3H (0.36mL, 5.52mmol), reacts 1-2h at room temperature, adds water quenching to go out after reaction completely, isolates organic
After layer, water is extracted three times with DCM, merges organic layer, normal phase silicagel column purifying (petroleum ether/dichloromethane) after being concentrated under reduced pressure,
HC-11 is obtained, its characterize data is as follows.
HC-11:1H NMR(400MHz,CDCl3) δ 7.58 (d, J=8.3Hz, 1H), 7.53 (d, J=7.8Hz, 1H),
7.24 (d, J=8.9Hz, 4H), 7.21 (d, J=7.8Hz, 1H) .6.97 (d, J=8.8Hz, 2H), 6.85 (dd, J=8.3,
2.2Hz, 1H), 6.81 (d, J=2.2Hz, 1H), 6.79 (d, J=8.8Hz, 2H), 6.71 (d, J=8.9Hz, 4H), 3.79 (s,
3H),3.72(s,3H),3.71(s,6H),2.46(s,3H)；13C NMR(100MHz,CDCl3)δ160.0,159.6,158.3,
155.6,152.3,139.0,138.4,135.1,132.6,132.4,130.4,128.9,121.1,120.3,118.8,
116.0,114.0,113.3,113.1,111.3,100.6,86.5,65.1,55.6,55.4,55.3,21.1.
Embodiment 7：
Anhydrous CH is dissolved under being protected by compound HC-11 (3.08mmol) nitrogen2Cl2It is added dropwise under (10mL), ice bath
BBr3(1.0M, 14.8mL, 14.8mmol), stirs 1-4h, is gradually brought to room temperature.After reaction completely water quenching is added under ice bath
Go out, be extracted with ethyl acetate three times, merge organic layer, normal phase silicagel column purifying (petrol ether/ethyl acetate), obtains after being concentrated under reduced pressure
To HC-3.With reference to the similar synthesis of HC-3, HC-4, HC-8, HC-9, HC-10 are obtained.
HC-3:Yellow oil；1H NMR(400MHz,CD3OD) δ 7.55 (dd, J=8.2,1.4Hz, 1H), 7.54 (dd,
J=7.6,1.3Hz, 1H), 7.21 (d, J=7.6Hz, 1H), 7.10 (d, J=7.1Hz, 4H), 6.86 (d, J=7.0Hz, 2H),
(s, the 3H) of 6.75 (d, J=8.2Hz, 1H), 6.72-6.65 (m, 3H), 6.58 (d, J=7.1Hz, 4H), 2.4313C NMR
(100MHz,CD3OD)δ159.0,158.7,157.3,156.8,153.6,140.0,139.1,135.5,133.6,132.5,
131.4,129.5,122.3,121.2,119.3,116.4,115.8,115.5,115.1,113.4,102.1,86.8,66.1,
21.0；ESIMS m/z 497.2[M+H]+.
HC-4:1H NMR(400MHz,CD3OD) δ 7.65 (d, J=7.5Hz, 1H), 7.60 (d, J=8.2Hz, 1H), 7.28
(t, J=7.5Hz, 1H), 7.21 (d, J=7.5Hz, 1H), 7.10 (d, J=8.7Hz, 4H), 6.88 (d, J=8.6Hz, 2H),
6.78 (dd, J=8.2,2.0Hz, 1H), 6.72 (d, J=2.0Hz, 1H), 6.69 (d, J=8.6Hz, 2H), 6.60 (d, J=
8.7Hz,4H)；ESIMS m/z 483.2[M+H]+.
HC-8:Yellow oil；UV(CH3OH)λmax(logε)209.0(7.25),272.0(6.92),317.5
(6.97),359.5(6.88)nm；IR(KBr)νmax 3366,2209,1674,1608,1568,1510,1221cm-1；1H NMR
(400MHz,CD3OD) δ 7.54 (d, J=8.0Hz, 1H), 7.68 (d, J=8.0Hz, 1H), 7.62 (d, J=8.0Hz, 1H),
6.78 (dd, J=8.0,2.0Hz, 1H), 6.71 (d, J=2.0Hz, 1H), 6.87 (d, J=8.4Hz, 2H), 6.70 (d, J=
8.4Hz, 2H), 7.10 (d, J=8.8Hz, 4H), 6.59 (d, J=8.8Hz, 4H), 5.69 (s, 3H), 3.40 (s, 6H)；13C
NMR(100MHz,CD3OD)δ159.6,159.4,157.9,157.0,153.6,142.9,138.2,135.0,133.7,
131.7,131.4,126.5,121.9,121.7,119.1,116.6,115.8,115.2,115.0,113.4,104.7,
102.8,85.2,66.2,55.1；HRESIMS m/z579.1807[M+Na]+(calcd for C36H28O6Na+,
579.1778).
HC-9:Yellow oil；UV(CH3OH)λmax(logε)206.5(7.63),288.5(7.44),297.5(7.44)
nm；IR(KBr)νmax 3316,1696,1608,1511,1469,1232cm-1；1H NMR(400MHz,CD3OD)δ7.07(d,J
=8.3Hz, 1H), 6.75 (d, J=8.3Hz, 1H), 7.95 (d, J=8.2Hz, 1H), 6.74 (dd, J=8.2,2.3Hz, 1H),
6.69 (d, J=2.3Hz, 1H), 6.83 (d, J=8.7Hz, 2H), 6.66 (d, J=8.7Hz, 2H), 7.11 (d, J=8.8Hz,
4H), 6.59 (d, J=8.8Hz, 4H)；13C NMR(100MHz,CD3OD)δ113.4,132.3,115.6,155.4,128.8,
132.1,125.5,115.1,157.9,113.1,156.5,66.4,154.3,88.5,94.7,133.4,116.4,159.0,
115.9,131.4,115.1,156.8,135.6；HRESIMS m/z 497.1406[M-H]-(calcd for C33H21O5 -,
497.1394).
HC-10:Yellow oil；UV(CH3OH)λmax(logε)208.0(7.71),287.5(7.47),301(7.47)
nm；IR(KBr)νmax 3325,2209,1697,1608,1590,1511,1453,1228cm-1；1H NMR(400MHz,CD3OD)
δ 6.87 (d, J=8.2Hz, 1H), 7.50 (d, J=8.2Hz, 1H), 7.47 (d, J=8.2Hz, 1H), 6.73 (dd, J=8.2,
2.4Hz, 1H), 6.68 (d, J=2.4Hz, 1H), 6.90 (d, J=8.2Hz, 2H), 6.69 (d, J=8.2Hz, 2H), 7.11 (d,
J=8.8Hz, 4H), 6.59 (d, J=8.8Hz, 4H)；13C NMR(100MHz,CD3OD)δ110.6,157.9,115.1,
120.4,134.2,132.7,120.4,115.4,157.8,113.4,156.7,66.1,154.9,83.8,101.9,133.7,
116.3,158.9,115.8,131.4,115.1,156.8,135.5；HRESIMS m/z 497.1413[M-H]-(calcd
for C33H21O5 -,497.1394).
Embodiment 8：The synthesis of HC-12
The HC-3 (1.48g, 3.0mmol) synthesized in embodiment 7 is dissolved in pyridine (15mL), add acetic anhydride (2.4mL,
24.0mmol).12h is stirred at room temperature, question response adds water (10mL) to be quenched afterwards completely.Use CH2Cl2Extraction three times, organic phase
Washed with water, 5%HCl and saturated nacl aqueous solution successively after merging, Na2SO4Dry.Organic phase concentrated under reduced pressure, normal phase silicagel column
Purifying (petroleum ether/dichloromethane=2:1) white powder HC-12, yield 68%, are obtained.
1H NMR(400MHz,CDCl3) δ 7.71 (d, J=8.2Hz, 1H), 7.64 (d, J=7.6Hz, 1H), 7.30 (d, J
=8.7Hz, 4H), 7.29 (d, J=7.6Hz, 1H), 7.12 (dd, J=8.2,2.0Hz, 1H), 7.04-7.01 (m, 5H), 6.91
(d, J=8.7Hz, 4H), 2.48 (s, 3H), 2.30 (s, 3H), 2.25 (s, 6H), 2.25 (s, 3H)；13C NMR(100MHz,
CDCl3)δ169.5,169.5,169.4,153.9,151.9,150.6,149.5,140.6,139.5,137.8,137.1,
132.5,130.2,129.5,122.0,121.4,120.9,120.9,120.9,120.2,120.0,119.1,100.5,87.1,
65.5,21.3,21.1.
Embodiment 9：The synthesis of HC-1, HC-2
The HC-12 (1.35g, 2.0mmol) that will synthesize in embodiment 8, NBS (0.39g, 2.2mmol), AIBN (0.03g,
0.2mmol) it is placed in two-neck bottle, nitrogen protection is lower to add anhydrous CCl4(10mL).Mixed liquor is in 80 DEG C of backflow 12h.React
Entirely, CH is added after being cooled to room temperature2Cl2(100mL) dilutes, and is washed with water, 5%HCl and saturated nacl aqueous solution successively,
Na2SO4Dry.Organic phase concentrated under reduced pressure, the bromide for obtaining is not purified, and is directly used in the next step.
The bromide and KOH (0.56g, 10mmol) of above-mentioned preparation are dissolved in 1,4-dioxane/H2O(2:1,15mL), 40 DEG C
Ethyl acetate dilution is added after lower stirring 1h. reactions completely, is washed with water and saturated nacl aqueous solution successively, Na2SO4Dry.Subtract
Pressure concentration organic phase, normal phase silicagel column purifying (petrol ether/ethyl acetate=2:1) HC-1 (0.60g, yield 59%), is obtained,
HC-2 (0.31g, yield 30%)
HC-1:Pale yellow oil,1H NMR(400MHz,CD3OD) δ 7.67 (d, J=7.8Hz, 1H), 7.60 (d, J=
8.2Hz, 1H), 7.49 (d, J=7.8Hz, 1H), 7.12 (d, J=8.6Hz, 4H), 6.89 (d, J=8.3Hz, 2H), 6.78 (d,
J=8.2Hz, 1H), 6.72 (s, 1H), 6.71 (d, J=8.3Hz, 2H), 6.60 (d, J=8.6Hz, 4H), 4.80 (s, 2H)；
ESIMS m/z 513.2[M+H]+.
HC-2:Yellow oil,1H NMR(400MHz,CD3OD) δ 10.45 (s, 1H), 7.87 (d, J=8.0Hz, 1H),
7.70 (d, J=8.0Hz, 1H), 7.67 (d, J=8.3Hz, 1H), 7.15 (d, J=8.7Hz, 4H), 6.89 (d, J=8.5Hz,
2H), 6.82 (dd, J=8.3,2.1Hz, 1H), 6.77 (d, J=2.1Hz, 1H), 6.72 (d, J=8.5Hz, 2H), 6.64 (d, J
=8.7Hz, 4H)；ESIMS m/z 511.2[M+H]+.
Embodiment 10：The synthesis of HC-6
The HC-2 (74mg, 0.15mmol) and NaH that will synthesize in embodiment 92PO4(59mg, 0.38mmol) is dissolved in DMSO
(1mL) and H2O (0.1mL), NaClO is slowly added under ice bath2The aqueous solution (0.1mL) of (41mg, 0.45mmol).At room temperature
Stirring 12h, adds saturated aqueous sodium carbonate to be quenched, ethyl acetate extraction after reaction completely.Water phase pH is adjusted with 0.5N HCl
=3, it is extracted with ethyl acetate (50mL × 3), merge organic layer, wash with water, Na2SO4Dry, be concentrated under reduced pressure to give HC-6
(63mg, yield 81%).
UV(CH3OH)λmax(logε)207.0(7.78),301.0(7.52)nm；IR(KBr)νmax 3278,2925,
2213,1697,1607,1511,1232cm-1；1H NMR(400MHz,CD3OD) δ 7.84 (d, J=7.9Hz, 1H), 7.69 (d, J
=7.9Hz, 1H), 7.67 (d, J=8.3Hz, 1H), 6.80 (dd, J=8.3,2.2Hz, 1H), 6.72 (d, J=2.2Hz, 1H),
6.83 (d, J=8.7Hz, 2H), 6.67 (d, J=8.7Hz, 2H), 7.11 (d, J=8.8Hz, 4H), 6.59 (d, J=8.8Hz,
4H)；13C NMR(100MHz,CD3OD)δ122.0,133.9,130.6,118.7,145.3,131.2,122.4,116.0,
159.9,113.3,158.7,66.4,154.3,86.8,103.0,133.9,116.2,159.1,115.8,131.4,115.2,
157.0,134.5,170.2；HRESIMS m/z 525.1346[M-H]-(calcd for C34H21O6 -,525.1344).
Embodiment 11：The synthesis of HC-4
Method one：With 2- bromobenzoic acids as raw material, successively according to the method for embodiment 1~7, HC-4 is can obtain.Data are shown in
Embodiment 7.
Method two：The HC-6 (38mg, 0.07mmol) synthesized in embodiment 10 is dissolved in DMSO (1mL), is added dropwise over dense
Hydrochloric acid (0.03mL).Reaction solution is stirred overnight at 100 DEG C.Water quenching is added to go out after being cooled to room temperature, ethyl acetate is extracted three times.Have
Machine is washed after mutually merging with saturated nacl aqueous solution, Na2SO4Dry.Organic phase concentrated under reduced pressure, normal phase silicagel column purifying (oil
Ether/ethyl acetate=2:1) HC-4 (20mg, yield 61%), is obtained.
Embodiment 12：The synthesis of HC-5
The HC-6 (21mg, 0.04mmol) and Ag that will synthesize in embodiment 102CO3(1mg, 0.004mmol) is dissolved in DMSO
In (1mL), it is stirred overnight at 120 DEG C, reaction is complete, adds saturated sodium bicarbonate aqueous solution to be quenched after being cooled to room temperature.Second
Acetoacetic ester extracts (20mL × 3), merges organic layer, uses saturated common salt water washing, Na2SO4Dry.Organic phase concentrated under reduced pressure, obtains
HC-5 (18mg, yield 85%).
UV(CH3OH)λmax(logε)208.0(6.94),225.0(6.83),320.0(6.88)nm；IR(KBr)νmax
3333,1694,1609,1577,1511,1230cm-1；1H NMR(400MHz,CD3OD) δ 8.27 (d, J=8.2Hz, 1H),
7.86 (d, J=8.2Hz, 1H), 7.73 (d, J=8.3Hz, 1H), 6.83 (dd, J=8.3,2.2Hz, 1H), 6.87 (d, J=
2.2Hz, 1H), 6.77 (brs, 1H), 7.41 (d, J=8.8Hz, 2H), 6.81 (d, J=8.8Hz, 2H), 7.12 (d, J=
8.8Hz, 4H), 6.70 (d, J=8.8Hz, 4H)；13C NMR(100MHz,CD3OD)δ136.1,118.4,131.2,119.8,
149.1,131.1,123.2,116.2,160.7,113.2,160.2,65.4,146.5,98.6,154.4,127.7,116.8,
160.7,124.6,131.0,116.0,157.5,134.2,164.9；HRESIMS m/z 549.1306[M+Na]+(calcd
for C34H22O6Na+,549.1309).
Embodiment 13：The synthesis of HC-7
With the bromo- 3- methyl -5- methoxy benzoic acids of 2- as raw material, according to the method for embodiment 1~7, HC-7 is can obtain.
Yellow oil；UV(CH3OH)λmax(logε)207.5(7.92),300.0(7.71)nm；IR(KBr)νmax
3241,2211,1607,1510,1225,1174cm-1；1H(400MHz,CD3OD) δ 6.94 (s, 1H), 7.88 (d, J=8.2Hz,
1H), 6.77 (dd, J=8.2,2.1Hz, 1H), 6.61 (d, J=2.1Hz, 1H), 6.76 (d, J=8.7Hz, 2H), 6.60 (d, J
=8.7Hz, 2H), 7.06 (d, J=8.6Hz, 4H), 6.52 (d, J=8.6Hz, 4H), 4.69 (s, 2H)；13C NMR(100MHz,
CD3OD)δ111.3,143.5,114.4,154.2,127.9,131.9,125.2,115.1,157.8,113.1,156.8,
66.4,155.8,85.6,100.1,133.3,116.5,159.4,115.6,131.4,115.1,156.8,135.5,63.5；
HRESIMS m/z 551.1457[M+Na]+(calcd for C34H24O6Na+,551.1465).
Embodiment 14：The synthesis of HC-13
Compound HC-1 (51mg, 0.10mmol) is dissolved in acetone (1.0mL), and K is successively added at room temperature2CO3(84mg,
0.60mmol) with MeI (36 μ L, 0.60mmol), it is stirred overnight at room temperature, adds water (10mL) to be quenched, is extracted with ethyl acetate
(5mL×3).Merge organic layer and be concentrated under reduced pressure, normal phase silicagel column purifying (petroleum ether:Ethyl acetate=10:1) water white oil is obtained
Shape thing HC-13 (46mg, yield 81%).
HC-13：1H NMR(400MHz,CDCl3) δ 7.65 (d, J=7.8Hz, 1H), 7.64 (d, J=8.3Hz, 1H),
7.46 (d, J=7.8Hz, 1H), 7.26 (d, J=8.9Hz, 4H), 6.99 (d, J=8.8Hz, 2H), 6.89 (dd, J=8.3,
2.3Hz, 1H), 6.85 (d, J=2.2Hz, 1H), 6.81 (d, J=8.8Hz, 2H), 6.74 (d, J=8.9Hz, 4H), 4.86 (s,
2H),3.80(s,3H),3.75(s,3H),3.73(s,6H)；13C NMR(100MHz,CDCl3)δ160.4,159.9,158.3,
155.8,152.5,141.2,140.4,134.8,132.7,131.9,130.3,127.3,120.8,119.5,119.2,
115.2,114.1,113.5,113.2,111.1,101.1,84.9,65.1,64.5,55.6,55.5,55.3；ESIMS m/z
569.2[M+H]+.
Embodiment 15：The synthesis of HC-14
Compound HC-1 (52mg, 0.10mmol) is dissolved in acetone (1.0mL), and K is successively added at room temperature2CO3(42mg,
0.30mmol) with MeI (12 μ L, 0.20mmol), 3h is stirred at room temperature, add water (10mL) to be quenched, be extracted with ethyl acetate
(5mL×3).Merge organic layer and be concentrated under reduced pressure, normal phase silicagel column purifying (petroleum ether:Ethyl acetate=4:1) obtain faint yellow
Grease HC-14 (11mg, yield 20%).
HC-14：UV(CH3OH)λmax(logε)206.5(7.69),288.0(7.49),399.5(7.49)nm；IR(KBr)
νmax 3387,2203,1605,1511,1248,833cm-1；1H NMR(400MHz,CD3OD) δ 7.73 (d, J=7.8Hz, 1H),
7.52 (d, J=7.8Hz, 1H), 7.69 (d, J=8.4Hz, 1H), 7.10 (d, J=8.9Hz, 4H), 6.97 (d, J=8.9Hz,
2H), 6.91 (dd, J=8.4,2.3Hz, 1H), 6.84 (d, J=8.9Hz, 2H), 6.80 (d, J=2.3Hz, 1H), 6.58 (d, J
=8.9Hz, 4H), 4.81 (s, 2H), 3.79 (s, 3H), 3.72 (s, 3H)；13C NMR(100MHz,CD3OD)δ161.7,
161.3,157.4,157.0,154.0,142.3,141.3,135.0,133.6,133.6,131.4,127.6,121.6,
120.6,119.9,116.7,115.3,115.0,114.5,112.0,102.1,85.9,66.3,63.6,55.9；55.8；
HRESIMS m/z 539.1859[M-H]-(calcd for C36H27O5 -,539.1864).
Embodiment 16：The synthesis of HC-15
Anhydrous CH is dissolved under HC-11 (1.70g, 3.08mmol) nitrogen protection obtained by embodiment 62Cl2(10mL), ice
BBr is added dropwise under bath3(1.0M, 18.5mL, 18.5mmol), stirs 1-4h, is gradually brought to room temperature.In ice after reaction completely
Bathe lower addition water quenching to go out, be extracted with ethyl acetate three times, merge organic layer, the rear normal phase silicagel column purifying that is concentrated under reduced pressure (petroleum ether/
Ethyl acetate=2:1~1:1) HC-15 (0.75g, yield 50%), is obtained.
HC-15：Yellow oil,1H NMR(400MHz,CD3OD) δ 7.70 (d, J=7.7Hz, 1H), 7.54 (d, J=
8.2Hz, 1H), 7.34 (d, J=7.9Hz, 1H), 6.99 (d, J=8.8Hz, 2H), 6.95 (d, J=8.7Hz, 2H), 6.69
(dd, J=8.2,2.2Hz, 1H), 6.59 (d, J=8.8Hz, 2H), 6.51 (d, J=2.2Hz, 1H), 6.46 (s, 1H), 6.25
(d, J=8.7Hz, 2H), 6.15 (d, J=8.8Hz, 2H), 6.09 (d, J=8.7Hz, 2H), 2.20 (s, 3H)；13C NMR
(100MHz,CD3OD)δ159.1,158.5,157.9,156.9,156.6,149.1,141.8,138.0,137.3,135.8,
135.6,133.4,132.6,131.4,131.2,130.9,130.4,128.7,121.1,120.7,115.6,115.3,
114.1,112.9,66.6,19.4；ESIMS m/z 575.1and 577.1[M-H]-.
Embodiment 17：The synthesis of HC-16
With the bromo- 5- methyl benzoic acids of 2- as raw material, HC-16 is can obtain according to the method for embodiment 2,3,5,6,7 successively.
HC-16：IR(KBr)νmax 3325,1651,1610,1591,1509,1466,1230cm-1；1H NMR(400MHz,
CD3OD) δ 7.48 (d, J=8.2Hz, 1H), 7.45 (d, J=7.6Hz, 1H), 7.06-7.00 (m, 2H), 6.94 (d, J=
8.8Hz, 4H), 6.75-6.70 (m, 2H), 6.60 (d, J=8.8Hz, 4H), 2.23 (s, 3H)；13C NMR(100MHz,CD3OD)
δ158.0,156.9,155.4,153.2,138.9,138.8,136.8,133.2,130.3,128.9,127.5,121.4,
119.7,115.7,115.4,114.1,65.1,21.7；ESIMS m/z381.1[M+H]+.
Embodiment 18：The synthesis of HC-17
With the bromo- 3- methyl benzoic acids of 2- as raw material, HC-17 is can obtain according to the method for embodiment 1,2,3,5,6,7 successively.
HC-17：IR(KBr)νmax 3251,1611,1509,1451,1251cm-1；1H NMR(400MHz,CD3OD)δ
7.57 (d, J=7.5Hz, 1H), 7.52 (d, J=8.1Hz, 1H), 7.25 (d, J=7.5Hz, 1H), 7.09 (d, J=8.4Hz,
4H), 6.72 (d, J=8.1Hz, 1H), 6.66 (s, 1H), 6.63 (d, J=8.4Hz, 4H), 2.33 (s, 3H)；13C NMR
(100MHz,CD3OD)δ159.0,158.3,156.9,151.0,142.9,137.3,133.4,131.7,131.6,131.2,
125.4,121.4,118.8,115.7,115.2,113.1,67.3,23.5；ESIMS m/z 459.1and 461.1[M+H]+.
Embodiment 19：The synthesis of HC-18, HC-19
With the bromo- 3- methyl benzoic acids of 2- as raw material, HC-17a is can obtain according to the method for embodiment 1,2,3,5,6 successively,
Method according still further to embodiment 9 can obtain HC-18a, HC-19a.
HC-18a:1H NMR(400MHz,CDCl3) δ 10.34 (s, 1H), 7.96 (d, J=7.9Hz, 1H), 7.73 (d, J=
7.9Hz, 1H), 7.67 (d, J=8.4Hz, 1H), 7.25 (d, J=8.8Hz, 4H), 6.89 (dd, J=8.4,2.2Hz, 1H),
6.80 (d, overlap, 1H), 6.78 (d, J=8.8Hz, 4H), 3.77 (s, 6H), 3.74 (s, 3H)；13C NMR(100MHz,
CDCl3)δ192.1,161.8,158.6,158.3,150.0,149.2,132.1,132.0,130.5,130.0,126.9,
122.2,118.6,114.3,113.3,110.8,66.2,55.6,55.3；ESIMS m/z515.1and 517.1[M+H]+.
HC-19a:1H NMR(400MHz,CDCl3) δ 7.67 (d, J=7.7Hz, 1H), 7.62 (d, J=8.4Hz, 1H),
7.49 (d, J=7.7Hz, 1H), 7.29 (d, J=8.8Hz, 4H), 6.88 (dd, J=8.4,2.2Hz, 1H), 6.84 (d, J=
2.2Hz, 1H), 6.79 (d, J=8.8Hz, 4H), 4.70 (s, 2H), 3.75 (s, 6H), 3.73 (s, 3H)；13C NMR(100MHz,
CDCl3)δ160.5,158.3,156.6,149.5,142.8,138.5,132.8,131.1,130.6,128.8,122.3,
120.8,118.4,113.5,113.1,110.9,66.1,65.4,55.5,55.2；ESIMS m/z517.1and 519.1[M+
H]+.
HC-18a, HC-19a can obtain HC-18, HC-19 according to the method for embodiment 7 respectively.
HC-18:White solid；IR(KBr)νmax 3409,1667,1610,1586,1510,1434,1239cm-1；1H
NMR(400MHz,CD3OD) δ 10.29 (s, 1H), 7.90 (d, J=7.9Hz, 1H), 7.81 (d, J=7.9Hz, 1H), 7.69 (d,
J=8.3Hz, 1H), 7.11 (d, J=8.8Hz, 4H), 6.80 (dd, J=8.3,2.2Hz, 1H), 6.71 (d, J=2.2Hz,
1H), 6.66 (d, J=8.8Hz, 4H)；13C NMR(100MHz,CD3OD)δ193.2,161.1,160.3,157.3,151.5,
151.1,133.0,132.4,131.6,131.3,130.0,123.4,119.3,116.6,115.5,113.1,67.3；ESIMS
m/z 473.0and 475.0[M+H]+.
HC-19:White solid；IR(KBr)νmax 3286,1610,1593,1510,1435,1351,1238cm-1；1H
NMR(400MHz,CD3OD) δ 7.68 (d, J=7.7Hz, 1H), 7.57 (d, J=8.2Hz, 1H), 7.42 (d, J=7.7Hz,
1H), 7.09 (d, J=8.7Hz, 4H), 6.75 (dd, J=8.2,2.1Hz, 1H), 6.68 (d, J=2.1Hz, 2H), 6.63 (d, J
=8.7Hz, 4H), 4.47 (s, 2H), 3.39 (s, 3H)；13C NMR(100MHz,CD3OD)δ159.4,158.6,157.0,
151.0,144.8,136.6,133.2,131.7,131.2,130.4,124.0,121.8,118.9,115.9,115.3,
113.1,75.5,67.3,58.6；ESIMS m/z 489.1and 491.1[M+H]+.
Embodiment 20：The synthesis of HC-22
With the bromo- 3- methyl benzoic acids of 2- as raw material, HC-22a. is can obtain according to the method for embodiment 1,2,3,5 successively
HC-22a (36mg, 0.09mmol) is dissolved in anhydrous CH2Cl2(1.0mL), triethyl silicane is sequentially added under ice bath
(28 μ L, 0.18mmol) and BF3·Et2O(22μL,0.18mmol).1h is stirred at 0 DEG C, saturated aqueous sodium carbonate is added
(1mL) is quenched.Separate organic layer, water layer CH2Cl2It is extracted twice.Merge organic layer, use saturated common salt water washing, Na2SO4It is dry
It is dry, it is concentrated under reduced pressure after purify (petroleum ether with normal phase silicagel column:Dichloromethane=5:1) HC-22b (23mg, yield 66%) is obtained
.IR(KBr)νmax 2957,2835,1607,1584,1508,1487,1244cm-1；1H NMR(400MHz,CDCl3)δ7.59
(d, J=8.4Hz, 1H), 7.53 (d, J=7.6Hz, 1H), 7.25 (d, J=7.6Hz, 1H), 6.97 (d, J=8.6Hz, 2H),
6.87 (dd, J=8.4,2.2Hz, 1H), 6.78 (d, J=8.6Hz, 2H), 6.77 (d, J=2.2Hz, 1H), 4.98 (s, 1H),
3.77(s,3H),3.76(s,3H),2.40(s,3H)；13C NMR(100MHz,CDCl3)δ159.9,158.5,150.5,
146.8,141.5,136.0,132.8,132.5,130.2,129.5,123.7,120.8,117.7,114.1,113.6,
110.8,55.9,55.6,55.3,22.9；ESIMS m/z 395.1and 397.1[M+H]+.
HC-22b (20mg, 0.05mmol) reacts according to the method for embodiment 7, obtains HC-22 (14mg, yield 76%)
.IR(KBr)νmax 3357,1611,1510,1483,1451,1242cm-1；1H NMR(400MHz,CD3OD)δ7.54(d,
Overlap, 2H), 7.25 (d, J=7.6Hz, 1H), 6.81 (d, J=8.4Hz, 2H), 6.75 (dd, J=8.2,2.2Hz, 1H),
6.64 (d, J=8.5Hz, 2H), 6.64 (d, J=2.2Hz, 1H) C, 4.87 (s, 1H), 2.36 (s, 2H)；13C NMR(100MHz,
CD3OD)δ158.7,157.0,152.1,147.9,143.2,136.4,132.8,132.7,131.1,130.3,124.2,
121.7,118.4,116.2,115.6,113.0,56.9,22.7；ESIMS m/z 367.0and 369.0[M+H]+.
Embodiment 21：Selaginpulvilin derivatives anti-inflammatory activity (to the inhibitory action of PDE4 enzymes)
Testing molecule is with containing restructuring PDE4D2 albumen, (detailed preparation method refers to have delivered and containing preparing the restructuring
The document of albumen：Bioorganic＆Medicinal Chemistry Letters, volume 22, the page number in 2012：3261–
3264), 20mM Tris-HCl, pH 7.5,2mM dithiothreitol (DTT) (dithiothreitol), 10mM MgCl2And 20,
000-30,000cpm's3H-cAMP is incubated 15 minutes at room temperature, and 0.2M ZnSO are then used respectively4and Ba(OH)2Stop anti-
Should, then using unreacted in the calculating instruments of PerkinElmer 2910 measurement supernatant3H-cGMP, each molecule is at least measured
Three times, the IC suppressed to PDE4D2 protein actives50Value is calculated and obtained by concentration determination and nonlinear regression.
Inhibitory activity test data such as table 1 (IC of the compounds of this invention to PDE450It is suppression when inhibiting rate reaches 50% to be worth
Formulation concentrations).
Inhibitory action (ICs of the compound HC-1-HC-30 of table 1. to PDE4 enzymes50,μM)
αPositive control
Claims (9)
1. a kind of preparation method of the derivative of natural products selaginpulvilin, it is characterised in that the natural products
Shown in the structural formula of the derivative of selaginpulvilin such as formula (I) or formula (II),
Wherein, R1It is alkyl, aldehyde radical, carboxyl, alcohol radical, hydroxyl, acyl group or hydrogen；R2It is hydrogen or hydroxyl；R3For alkoxy, acyl group or
Hydroxyl；R4It is halogen, fragrant acetenyl, phenyl or substituted-phenyl, aromatic ethylene base；R5It is hydrogen, hydroxyl, phenyl or substituted-phenyl；R6For
Hydrogen, phenyl or substituted-phenyl；Substitution base is selected from alkoxy, acyl group or hydroxyl；
The preparation method specifically includes following steps：
S1. the bromobenzoic acid class compound shown in formula (III) reacts with iodoacetic acid, obtains chemical combination of the structural formula as shown in formula (IV)
Thing；
S2. the compound by step S1 gained as shown in structure formula (IV) reacts with iodomethane, phenylboronic acid compound successively
To compound of the structural formula as shown in formula (V)；Wherein, X is bromine or hydrogen；
S3. compound of the structural formula for step S2 being obtained as shown in formula (V) is reacted with methanesulfonic acid, obtains structural formula such as formula
(VI) compound shown in；Wherein, X is bromine or hydrogen；
S4. when X is bromine, by compound of the structural formula as shown in formula (VI) and fragrant acetylene compound reaction, structural formula is obtained
Compound as shown in formula (VII)；
S5. compound of the structural formula for step S4 being obtained as shown in formula (VII) is carried out with RMgBr magnesium bromide class compound
After reaction, compound of the structural formula as shown in formula (VIII) is obtained；
S6. after compound of the structural formula for step S5 being obtained as shown in formula (VIII) is reacted with methyl phenyl ethers anisole class compound,
Obtain compound of the structural formula as shown in formula (I)；
S7. compound of the structural formula for step S6 being obtained as shown in formula (I) by after de- alkyl, bromo acylation reaction, then with
Sodium dihydrogen phosphate and sodium chlorite react, and are finally reacted with silver carbonate, obtain compound of the structural formula as shown in formula (II).
2. preparation method according to claim 1, it is characterised in that R1It is hydrogen, carboxyl, aldehyde radical, hydroxyl, methylol, C1~5
Alkyl, dimethoxymethane base, acetyl group, methoxy or ethoxy；R2It is hydrogen or hydroxyl；R3It is methoxyl group, hydroxyl, acetyl group；
R4For halogen, to Methoxy-phenylacetylene base, para hydroxybenzene acetenyl, to acetylbenzene acetenyl, 4- hydroxy phenyls, (Z) -1-
Bromo- 2- (p-hydroxybenzene) vinyl,；R5It is hydrogen, hydroxyl, 4- hydroxy phenyls, p-methoxyphenyl or to acetylphenyl；R6
It is hydrogen, 4- hydroxy phenyls, p-methoxyphenyl or to acetylphenyl.
3. preparation method according to claim 1, it is characterised in that reaction temperature is 80~120 DEG C in S1 steps, reaction
Time is 20~30h.
4. preparation method according to claim 1, it is characterised in that reaction temperature is 60~70 DEG C in S3 steps, reaction
Time is 5~7h.
5. a kind of derivative of natural products selaginpulvilin, it is characterised in that the natural products
Shown in the structural formula of the derivative of selaginpulvilin such as formula (I) or formula (II),
Wherein, R1It is alkyl, aldehyde radical, carboxyl, alcohol radical, hydroxyl, acyl group or hydrogen；R2It is hydrogen or hydroxyl；R3For alkoxy, acyl group or
Hydroxyl；R4It is halogen, fragrant acetenyl, phenyl or substituted-phenyl, aromatic ethylene base；R5It is hydrogen, hydroxyl, phenyl or substituted-phenyl；R6For
Hydrogen, phenyl or substituted-phenyl；Substitution base is selected from alkoxy, acyl group or hydroxyl.
6. derivative according to claim 5, it is characterised in that R1It is hydrogen, carboxyl, aldehyde radical, hydroxyl, methylol, C1~5Alkane
Base, dimethoxymethane base, acetyl group, methoxy or ethoxy；R2It is hydrogen or hydroxyl；R3It is methoxyl group, hydroxyl, acetyl group；R4
For halogen, to Methoxy-phenylacetylene base, para hydroxybenzene acetenyl, bromo- to acetylbenzene acetenyl, 4- hydroxy phenyls, (Z) -1-
2- (p-hydroxybenzene) vinyl,；R5It is hydrogen, hydroxyl, 4- hydroxy phenyls, p-methoxyphenyl or to acetylphenyl；R6For
Hydrogen, 4- hydroxy phenyls, p-methoxyphenyl or to acetylphenyl.
7. derivative according to claim 6, it is characterised in that work as R2During for hydrogen, R1Asynchronously for hydrogen, methyl, aldehyde radical or
Methylol；
Work as R6During for 4- hydroxy phenyls, R1It is asynchronously methyl or methylol.
8. application of the derivative described in claim 7 in anti-inflammatory drug is prepared.
9. application according to claim 7, it is characterised in that the medicine is PDE4 suppressive anti-inflammatory drugs.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838465A (en) * | 2011-06-24 | 2012-12-26 | 沈阳药科大学 | New compound selaginellin M with anticancer activity, and uses thereof |
| CN103588616A (en) * | 2013-10-18 | 2014-02-19 | 中山大学 | Selaginella pulvinata extract as well as preparation method and applications thereof |
| CN104817447A (en) * | 2015-03-10 | 2015-08-05 | 沈阳药科大学 | Preparation method for selaginellin M |
| CN105037124A (en) * | 2015-03-10 | 2015-11-11 | 沈阳药科大学 | Preparation method of selaginellin N |
-
2016
- 2016-11-23 CN CN201611043917.5A patent/CN106748667B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838465A (en) * | 2011-06-24 | 2012-12-26 | 沈阳药科大学 | New compound selaginellin M with anticancer activity, and uses thereof |
| CN103588616A (en) * | 2013-10-18 | 2014-02-19 | 中山大学 | Selaginella pulvinata extract as well as preparation method and applications thereof |
| CN104817447A (en) * | 2015-03-10 | 2015-08-05 | 沈阳药科大学 | Preparation method for selaginellin M |
| CN105037124A (en) * | 2015-03-10 | 2015-11-11 | 沈阳药科大学 | Preparation method of selaginellin N |
Non-Patent Citations (2)
| Title |
|---|
| XIN LIU等: "Selaginpulvilins A-D, New Phosphodiesterase-4 Inhibitors with an Unprecedented Skeleton from Selaginella pulvinata", 《ORG. LETT.》 * |
| 刘信等: "新型天然PDE4抑制剂的发现与研究", 《中国化学会第十届全国天然有机化学学术会议论文集》 * |
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