CN109503697A - 3- (L-phenylalanine)-pentacyclic triterpene derivative and its synthetic method and application - Google Patents
3- (L-phenylalanine)-pentacyclic triterpene derivative and its synthetic method and application Download PDFInfo
- Publication number
- CN109503697A CN109503697A CN201910022937.1A CN201910022937A CN109503697A CN 109503697 A CN109503697 A CN 109503697A CN 201910022937 A CN201910022937 A CN 201910022937A CN 109503697 A CN109503697 A CN 109503697A
- Authority
- CN
- China
- Prior art keywords
- compound
- synthetic method
- crude product
- phenylalanine
- heated
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a series of 3- (L-phenylalanine)-pentacyclic triterpene derivative and its synthetic method and applications.The pentacyclic triterpene derivative is 2 3- (L-phenylalanine)-oleanolic acid derivates and 2 3- (L-phenylalanine)-Enoxolone derivatives, specifically reacts to obtain 3- (L-phenylalanine)-oleanolic acid derivate or 3- (L-phenylalanine)-Enoxolone derivative with Boc-L- phenylalanine, dicyclohexylcarbodiimide and 4-dimethylaminopyridine with oleanolic acid or enoxolone；They are reacted with trifluoroacetic acid respectively again obtains other 2 derivatives.The in vitro test of applicant the result shows that, they have good proliferation inhibition activity to certain tumor cell lines, have preferable potential medical value, are expected to be used for the preparation of various anti-tumor drugs.
Description
Technical field
The present invention relates to pentacyclic triterpene derivatives, and in particular to 3- (L-phenylalanine)-pentacyclic triterpene derivative and its conjunction
At methods and applications.
Background technique
Pentacyclic triterpenoid is widely distributed in nature, is much to commonly use medium-height grass the effective elements of the medicine, by its alkane
The difference of hydrocarbon structure skeleton is broadly divided into: oleanane type, black bearberry alkane type and lupinane type etc..Pentacyclic triterpenoid
Generally there is extensive bioactivity, such as reducing blood sugar and blood lipid, anti-inflammatory, antitumor, AntiHIV1 RT activity, antiviral.Oleanolic acid is as shield
Liver slice has listed nearly 40 years in China.
Amino acid plays important as the basic composition unit of biological function macro-molecular protein in life process
Effect.Tumour cell metabolism is vigorous, the state for needing a large amount of nutriment cell high speed is maintained to breed, wherein amino acid
It is its necessary nutriment.
L-phenylalanine belongs to essential amino acid, and human body cannot be synthesized independently, it is necessary to be absorbed from food.At present still
It there are no the relevant report that oncotherapy is used for about 3- (L-phenylalanine)-pentacyclic triterpene derivative.
Summary of the invention
The technical problem to be solved in the present invention is to provide a series of 3- of structure novels (L-phenylalanine)-pentacyclic triterpenes to spread out
Biology and their synthetic method and application.
It can the present invention relates to 3- shown in following formula 1-4 (L-phenylalanine)-pentacyclic triterpene derivative and its pharmaceutically connect
The salt received:
The present invention also provides above-mentioned 3- (L-phenylalanine)-pentacyclic triterpene derivative synthetic methods, comprising:
The synthetic method of compound 1 mainly comprises the steps that take oleanolic acid and Boc-L- phenylalanine to be dissolved in organic
In solvent, dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) is added, it is anti-under the conditions of being heated or not heated
It answers, after the reaction was completed, filtrate is collected in resulting material filtering, and recycling design obtains 1 crude product of compound；
The synthetic method of compound 2 mainly comprises the steps that and takes compound 1 and trifluoroacetic acid exist in organic solvent
Or under conditions of being not present, reacted under the conditions of being heated or not heated, after the reaction was completed, alkalinity is added dropwise in Xiang Fanying resulting material
Solution, until bubble-free generates；Resulting material is extracted with extractant, is collected organic phase, is spin-dried for, is changed after washed, dry
Close 2 crude product of object；
It is organic to mainly comprise the steps that extracting liquorice hypo acid and Boc-L- phenylalanine are dissolved in for the synthetic method of compound 3
In solvent, dicyclohexylcarbodiimide and 4-dimethylaminopyridine is added, is reacted under the conditions of being heated or not heated, reaction is completed
Afterwards, resulting material filters, and collects filtrate, and recycling design obtains 3 crude product of compound；
The synthetic method of compound 4 mainly comprises the steps that and takes compound 3 and trifluoroacetic acid exist in organic solvent
Or under conditions of being not present, reacted under the conditions of being heated or not heated, after the reaction was completed, alkalinity is added dropwise in Xiang Fanying resulting material
Solution, until bubble-free generates；Resulting material is extracted with extractant, is collected organic phase, is spin-dried for, is changed after washed, dry
Close 4 crude product of object；
Wherein, the organic solvent is one in methylene chloride, chloroform, methanol, tetrahydrofuran and ethyl acetate
Kind or two or more combinations；The extractant is methylene chloride, chloroform or ethyl acetate.
In the synthetic method of above-mentioned each compound, reaction is preferably carried out under the conditions of being less than or equal to 50 DEG C, more excellent
Choosing is to carry out at normal temperature.Reaction whether completely available thin-layer chromatography (TLC) tracing detection.When reaction carries out under normal temperature conditions
When, the time respectively reacted is normally controlled in 1-24h.
In the synthetic method of above-mentioned each compound, the alkaline solution being related to can be the water-soluble of existing common alkaline matter
Liquid is preferably selected from one of aqueous sodium carbonate, sodium bicarbonate aqueous solution, wet chemical and potassium bicarbonate aqueous solution
Or two or more combination；More preferably saturated aqueous sodium carbonate, saturated sodium bicarbonate aqueous solution, unsaturated carbonate aqueous solutions of potassium
Or saturated potassium hydrogen carbonate aqueous solution.
In the synthetic method of above-mentioned each compound, the molar ratio of each reaction raw materials is their stoichiometric ratio.?
In the synthetic method of compound 1 or compound 3, dicyclohexylcarbodiimide is used as condensing agent, and additional amount is preferably neat
1-5 times of pier tartaric acid or enoxolone mole；And 4-dimethylaminopyridine is used as catalyst, additional amount is preferably neat
The 10-20% of pier tartaric acid or enoxolone mole.
In the synthetic method of above-mentioned each compound, the dosage of organic solvent is usually that can dissolve the raw material for participating in reaction
It is advisable.In the synthetic method of compound 2 or compound 4, trifluoroacetic acid is used as reaction raw materials to use and also can be used as solvent and make
With when trifluoroacetic acid is used as reaction raw materials and solvent in use, its additional amount accordingly increases now.
It is the crude product of each compound made from above-mentioned synthetic method, existing conventional purification process can be used, they are carried out
It purifies to improve the purity of each compound.Silica gel column chromatography is generallyd use to be purified.When by 1 crude product of compound or compound 3
On crude product when silica gel column chromatography, the eluant, eluent for elution is the mixed solvent consisted of petroleum ether and ethyl acetate, wherein stone
The volume ratio of oily ether and ethyl acetate is preferably 5-10:1, further preferably 5-8:1.When by 2 crude product of compound or compound 4
On crude product when silica gel column chromatography, the eluant, eluent for elution is preferably the mixed solvent consisted of petroleum ether and ethyl acetate,
The volume ratio of middle petroleum ether and ethyl acetate is preferably 1-5:1, further preferably 1-3:1.
In order to be further reduced the burden of silicagel column, dichloro first preferably is dispersed by 1 crude product of compound or 3 crude product of compound
In methane, chloroform or ethyl acetate, through water, saturated common salt water washing, after dry (anhydrous sodium sulfate or anhydrous magnesium sulfate are dry)
It is spin-dried for, gained residue carries out column chromatography again.
In synthetic method of the present invention, in the extracting operation that is related to, the usually first water of the organic phase collected after extraction, saturation
Saline solution is washed, and is spin-dried for again after being dried later with anhydrous sodium sulfate or anhydrous magnesium sulfate.
The present invention further comprises that any compound or its pharmaceutically acceptable salt are anti-in preparation in above compound 1-4
Application in tumour medicine.
The present invention further includes a kind of pharmaceutical composition, containing in the above compound 1-4 for treating upper effective dose
Any compound or its pharmaceutically acceptable salt.The dosage form of described pharmaceutical composition can be pharmaceutically acceptable dosage form,
Such as liquid dosage form, solid dosage forms or semisolid dosage form.
Compared with prior art, the present invention provides a series of 3- of structure novels (L-phenylalanine)-pentacyclic triterpenes to spread out
Biology and its synthetic method, it is good that the in vitro test test result of applicant shows that they have certain tumor cell lines
Proliferation inhibition activity has preferable potential medical value, is expected to be used for the preparation of various anti-tumor drugs.
Specific embodiment
The present invention is described in further detail combined with specific embodiments below, content to better understand the invention, but
The present invention is not limited to following embodiments.
Embodiment 1: the synthesis of compound 1
Oleanolic acid (2.00g, 4.38mmol) and Boc-L- phenylalanine (1.74g, 6.57mmol) is taken to be dissolved in CH2Cl2
In (50mL), DCC (1.80g, 8.77mmol), DMAP (0.10g, 0.87mmol) are sequentially added, is stirred to react under room temperature
For 24 hours, gained reactant material filters, and filter cake is washed with methylene chloride (20mL), collects filtrate, and decompression is spin-dried for, gained residue point
It dissipates in EtOAc (200mL), successively uses water, saturated common salt water washing, anhydrous sodium sulfate dries, filters, and filtrate is spin-dried for obtaining thick
Product.Silica gel column chromatography separates (eluant, eluent: V on crude productPetroleum ether:VEthyl acetate=8:1-5:1), obtain compound 1 (1.98g,
64.0%, white solid).
Yield:1.98g, 64.0%, white solid；Rf=0.72 (Petroleum ether:EtOAc=2:1)
.m.p.116-118℃.1H NMR(500MHz,CDCl3):δ0.73(s,3H,CH3),0.79(s,6H,2×CH3),0.90,
0.91,0.92,1.12(4s,each 3H,4×CH3),1.38(s,9H,3×CH3),0.83-2.00(m,22H),2.79-2.83
(m,1H,H-18),2.99-3.15(m,2H,phCH2), 4.49-4.58 (m, 2H, H-3, NCHCOO), 4.91 (d, J=8.6Hz,
1H, NH), 5.26 (t, J=3.6Hz, 1H, H-12), 7.16-7.30 (m, 5H, Ar-H) .13C NMR (125MHz, CDCl3): δ
15.6,16.0,17.4,18.4,23.2,23.7,23.9,26.2,28.0,28.4,28.6,31.0,32.7,32.8,33.3,
34.1,37.2,38.0,38.3,38.8,39.6,41.2,41.8,46.1,46.8,47.8,54.9,55.6,80.1,82.8,
122.8,127.2,128.8,129.7,136.4,143.9,155.4,172.2,184.2.HRMS(ESI)m/z:calcd for
C44H65NO6Na[M+Na]+726.4710；found 726.4672.
Embodiment 2: the synthesis of compound 1
Oleanolic acid (2.00g, 4.38mmol) and Boc-L- phenylalanine (1.74g, 6.57mmol) is taken to be dissolved in MeOH
In (50mL), DCC (1.80g, 8.77mmol), DMAP (0.10g, 0.87mmol) are sequentially added, is stirred to react under room temperature
10h, the filtering of gained reactant material, filter cake are washed with MeOH (20mL), collect filtrate, decompression is spin-dried for, silica gel on gained residue
Column chromatography for separation (eluant, eluent: VPetroleum ether:VEthyl acetate=8:1-5:1), obtain white solid (1.21g, 40.0%).
Products therefrom is characterized through nucleus magnetic hydrogen spectrum, is determined as compound 1.
Embodiment 3: the synthesis of compound 2
Compound 1 (0.20g, 0.28mmol) is taken to be dissolved in CH2Cl2In (15mL), it is added TFA (0.6mL, 0.2mL/1h), room
It is stirred to react 3h under the conditions of temperature, saturated sodium bicarbonate aqueous solution is added dropwise in Xiang Fanying resulting material until bubble-free generation, is used
CH2Cl2(3 × 50mL) extraction merges organic layer, saturated common salt water washing, and anhydrous sodium sulfate dries, filters, and filtrate is spin-dried for slightly
Product.Silica gel column chromatography separates (eluant, eluent: V on crude productPetroleum ether:VEthyl acetate=3:1-1:1), obtain compound 2 (0.11g,
64.0%, white solid).
Yield:0.11g, 64.0%, white solid；Rf=0.31 (Petroleum ether:EtOAc=1:1)
.m.p.144-146℃.1H NMR(400MHz,CDCl3):δ0.74,0.80,0.82,0.89,0.921,0.926,1.12(7s,
each 3H,7×CH3), 0.84-2.00 (m, 22H), 2.79-2.86 (m, 2H, H-18, phCH), 3.14 (dd, J=5.4,
13.6Hz, 1H, phCH), 3.74-3.77 (m, 1H, NCHCOO), 4.50-4.54 (m, 1H, H-3), 5.26 (t, J=3.6Hz,
1H,H-12),7.19-7.30(m,5H,Ar-H).13C NMR(100MHz,CDCl3):δ15.6,17.0,17.4,18.4,23.2,
23.7,23.8,23.9,26.2,28.0,28.4,31.0,32.81,32.89,33.4,34.1,37.2,38.1,38.3,39.6,
41.2,41.3,41.9,46.2,46.8,47.8,55.6,56.1,82.2,122.6,127.1,128.9,129.6,137.4,
144.1,174.7,183.5.HRMS(ESI)m/z:calcd for C39H58NO4[M+H]+604.4366；found
604.4360.
Embodiment 4: the synthesis of compound 2
Take compound 1 (0.20g, 0.28mmol) and TFA (10mL) in being stirred to react 1h under room temperature, to reaction gained
Saturated aqueous sodium carbonate is added dropwise in material until bubble-free generation, uses CH2Cl2(3 × 50mL) extraction merges organic layer, saturation
Brine It, anhydrous sodium sulfate dry, filter, and filtrate is spin-dried for obtaining crude product.Silica gel column chromatography separation (elution on crude product
Agent: VPetroleum ether:VEthyl acetate=3:1-1:1), obtain white solid (0.08g, 45.0%).
Products therefrom is characterized through nucleus magnetic hydrogen spectrum, is determined as compound 2.
Embodiment 5: the synthesis of compound 3
Extracting liquorice hypo acid (0.25g, 0.53mmol) and Boc-L- phenylalanine (0.21g, 0.79mmol) are dissolved in CH2Cl2
It in (25mL), sequentially adds DCC (0.16g, 0.79mmol), DMAP (9.6mg, 0.079mmol) is stirred to react under room temperature
For 24 hours, gained reactant material filters, and filter cake is washed with methylene chloride (20mL), and filtrate decompression is spin-dried for, and residue is dispersed in CH2Cl2
In (100mL), water, saturated common salt water washing are successively used, anhydrous sodium sulfate dries, filters, and filtrate is spin-dried for obtaining crude product.Crude product
Upper silica gel column chromatography separates (eluant, eluent: VPetroleum ether:VEthyl acetate=8:1-5:1), obtaining compound 3, (0.21g, 56.8%, white is solid
Body).
Yield:0.21g, 56.8%, white solid；Rf=0.533 (Petroleum ether:EtOAc=1:1)
.m.p.132-134℃.1H NMR(500MHz,CDCl3):δ0.79,0.80,0.82,1.11,1.13,1.21,1.36(7s,
each 3H,7×CH3),1.38(s,9H,3×CH3),1.00-2.21(m,19H),2.35(s,1H,H-9),2.77-2.80(m,
1H,H-18),3.010-3.13(m,2H,phCH2), 4.50-4.59 (m, 2H, H-3, NCHCOO), 4.91 (d, J=8.6Hz,
1H,NH),5.71(s,1H,H-12),7.16-7.29(m,5H,Ar-H).13C NMR(125MHz,CDCl3):δ16.6,17.0,
17.6,19.0,23.6,23.7,25.0,25.7,26.7,26.8,28.3,28.6,28.7,28.8,31.2,32.1,33.0,
33.8,37.2,38.0,38.3,38.7,39.0,41.2,43.5,44.1,45.7,48.5,54.9,55.3,61.9,80.1,
82.5,127.2,128.7,128.8,129.7,136.4,155.4,169.9,172.1,181.7,200.5.HRMS(ESI)m/
z:calcd for C44H63NO7Na[M+Na]+740.4502；found 740.4470.
Embodiment 6: the synthesis of compound 3
Extracting liquorice hypo acid (0.25g, 0.53mmol) and Boc-L- phenylalanine (0.21g, 0.79mmol) are dissolved in THF
It in (25mL), sequentially adds DCC (0.16g, 0.79mmol), DMAP (9.6mg, 0.079mmol) is stirred to react under room temperature
10h, the filtering of gained reactant material, filter cake are washed with THF (20mL), and filtrate decompression is spin-dried for, and residue is dispersed in CH2Cl2
In (100mL), water, saturated common salt water washing are successively used, anhydrous sodium sulfate dries, filters, and filtrate is spin-dried for obtaining crude product.Crude product
Upper silica gel column chromatography separates (eluant, eluent: VPetroleum ether:VEthyl acetate=8:1-5:1), obtain white solid (0.19g, 51.8%).
Products therefrom is characterized through nucleus magnetic hydrogen spectrum, is determined as compound 3.
Embodiment 7: the synthesis of compound 4
Compound 3 (1g, 1.39mmol) is taken to be dissolved in CH2Cl2In (15mL), TFA (2mL, 1mL/1h) is added at room temperature, room
It is stirred to react 2h under the conditions of temperature, saturated potassium hydrogen carbonate aqueous solution is added dropwise in Xiang Fanying resulting material until bubble-free generation, is used
EtOAc (3 × 50mL) extraction merges organic layer, saturated common salt water washing, and anhydrous magnesium sulfate dries, filters, and filtrate is spin-dried for slightly
Product.Silica gel column chromatography separates (eluant, eluent: V on crude productPetroleum ether:VEthyl acetate=3:1-1:1), obtain compound 4 (0.82g,
95.00%, white solid).
Yield:0.82g, 95.00%, white solid；Rf=0.21 (Petroleum ether:EtOAc=1:1)
.m.p.152-154℃.1H NMR(500MHz,CDCl3):δ0.80,0.81,0.84,1.11,1.14,1.19,1.36(7s,
each 3H,7×CH3),1.00-2.20(m,19H),2.35(s,1H,H-9),2.77-2.81(m,1H,H-18),2.87-
3.19(m,2H,phCH2), 3.82-3.84 (m, NCHCOO), 4.56 (dd, J=4.8,11.5Hz, 1H, H-3), 5.70 (s, 1H,
H-12),7.21-7.31(m,5H,Ar-H).13C NMR(125MHz,CDCl3):δ16.7,17.1,17.6,19.0,23.7,
23.8,26.7,26.8,28.4,28.83,28.88,31.3,32.2,33.0,37.2,38.1,38.4,39.0,40.5,41.3,
43.5,44.1,45.7,48.6,55.3,55.8,61.9,82.4,127.3,128.7,129.0,129.7,136.8,169.8,
173.7,181.3,200.4.HRMS(ESI)m/z:calcd for C39H56NO5[M+H]+618.4159；found
618.4120.
Embodiment 8: the synthesis of compound 4
Embodiment 7 is repeated, unlike: CH is substituted with EtOAc2Cl2As solvent, reaction carries out under the conditions of 50 DEG C,
It is remaining constant.Finally obtain white solid (0.71g, 85.8%).
Products therefrom is characterized through nucleus magnetic hydrogen spectrum, is determined as compound 4.
Experimental example: compound 1-4 of the present invention tests the proliferation inhibition activity of various tumor cell strains:
1, cell strain and cell culture
Human bladder cancer cell T24, people's non-small lung cancers cell A549, gastric carcinoma cells MGC-803, human liver cancer are selected in this experiment
5 kinds of human cell's strains such as cell HepG2, Human normal hepatocyte HL-7702.
All cell strains are cultivated in the RPMI-1640 culture solution containing 10% calf serum, 100U/mL streptomysin, are set
37 DEG C of 5%CO containing volumetric concentration2It is cultivated in incubator.
2, the preparation of untested compound
Purity >=95% of test medicine used is configured to 200 μ after diluting its DMSO liquid storage with physiological buffer
The whole solution of mol/L, wherein concentration≤1% of cosolvent DMSO test under the concentration compound to various growth of tumour cell
Obtain inhibition level.
3, cell growth inhibition test (mtt assay)
(1) tumour cell of logarithmic growth phase is matched after trypsin digestion with the culture solution containing 10% calf serum
Being set to the cell suspension that concentration is 5000/mL makes cell concentration to be measured extremely not have 190 μ L of hole to be inoculated in 96 well culture plates
Every 1000~10000/ hole of hole (edge hole is filled with sterile PBS)；
(2) 5%CO2, 37 DEG C are incubated for for 24 hours, until cell monolayer is paved with bottom hole, the drug 10 of a certain concentration gradient is added in every hole
μ L, each concentration gradient set 4 multiple holes；
(3) 5%CO2, 37 DEG C of incubation 48h, until being observed under inverted microscope；
(4) the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L is added in every hole, continues to cultivate 4h；
(5) culture is terminated, culture solution in hole is carefully sucked, the DMSO that 150 μ L are added in every hole sufficiently dissolves first a ceremonial jade-ladle, used in libation precipitating, vibration
It swings after device mixes, with wavelength is 570nm in microplate reader, reference wavelength is the OD value that 450nm measures each hole；
(6) it is arranged zeroing hole (culture medium, MTT, DMSO) simultaneously, (the drug dissolution of cell, same concentrations is situated between control wells
Matter, culture solution, MTT, DMSO).
(7) according to the OD value (OD value) measured, to judge living cells quantity, OD value is bigger, and cell activity is stronger.Benefit
With formula:
Growth of tumour cell inhibiting rate (%)=[(1- experimental group mean OD value)/(control group mean OD value)] × %；
IC50Measurement: utilizing above method, and concentration gradient must be arranged in every kind of compound, wherein dense containing multiple (general 5-8)
3~5 secondary orifices must be also arranged in degree, each concentration, and experiment obtains the inhibiting rate of each various concentration, then falls into a trap in SPSS software
Calculate the IC of compound50Value, as a result as described in Table 1.
Table 1: IC of each compound to different cell strains50It is worth (μM)
Note: experimental data is the average value of 3 experiments.IC50Value is lower, illustrates that the compound inhibits growth of tumour cell
Activity is stronger.
Claims (9)
1. 3- shown in following formula 1-4 (L-phenylalanine)-pentacyclic triterpene derivative and its pharmaceutically acceptable salt:
2. 3- described in claim 1 (L-phenylalanine)-pentacyclic triterpene derivative synthetic method, comprising:
The synthetic method of compound 1 mainly comprises the steps that and oleanolic acid and Boc-L- phenylalanine is taken to be dissolved in organic solvent
In, dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) is added, is reacted under the conditions of being heated or not heated,
After the reaction was completed, resulting material filters, and collects filtrate, and recycling design obtains 1 crude product of compound；
The synthetic method of compound 2 mainly comprises the steps that and takes compound 1 and trifluoroacetic acid, in organic solvent presence or not
It under the conditions of existing, is reacted under the conditions of being heated or not heated, it is molten that alkalinity is added dropwise after the reaction was completed, in Xiang Fanying resulting material
Liquid, until bubble-free generates；Resulting material is extracted with extractant, is collected organic phase, is spin-dried for after washed, dry, obtains chemical combination
2 crude product of object；
The synthetic method of compound 3 mainly comprises the steps that extracting liquorice hypo acid and Boc-L- phenylalanine are dissolved in organic solvent
In, dicyclohexylcarbodiimide and 4-dimethylaminopyridine is added, is reacted under the conditions of being heated or not heated, after the reaction was completed,
Resulting material filtering, collects filtrate, and recycling design obtains 3 crude product of compound；
The synthetic method of compound 4 mainly comprises the steps that and takes compound 3 and trifluoroacetic acid, in organic solvent presence or not
It under the conditions of existing, is reacted under the conditions of being heated or not heated, it is molten that alkalinity is added dropwise after the reaction was completed, in Xiang Fanying resulting material
Liquid, until bubble-free generates；Resulting material is extracted with extractant, is collected organic phase, is spin-dried for after washed, dry, obtains chemical combination
4 crude product of object；
Wherein, the organic solvent be selected from one of methylene chloride, chloroform, methanol, tetrahydrofuran and ethyl acetate or
Two or more combinations；The extractant is methylene chloride, chloroform or ethyl acetate.
3. synthetic method according to claim 2, it is characterised in that: in the synthetic method of each compound, react low
In or equal to carrying out under the conditions of 50 DEG C.
4. synthetic method according to claim 2, it is characterised in that: the alkaline solution is water-soluble selected from sodium carbonate
The combination of one or more of liquid, sodium bicarbonate aqueous solution, wet chemical and potassium bicarbonate aqueous solution.
5. the synthetic method according to any one of claim 2-4, it is characterised in that: in the synthetic method of each compound
In, it further include the purification step purified to each crude compound.
6. synthetic method according to claim 5, it is characterised in that: the purification step are as follows: by 1 crude product of compound or
2 crude product of compound or 3 crude product of compound or 4 crude product of compound carry out column chromatography, to obtain compound 1 or compound after purification
2 or compound 3 or compound 4.
7. synthetic method according to claim 6, it is characterised in that: carried out by 1 crude product of compound or 3 crude product of compound
It before column chromatography, first disperses 1 crude product of compound or 3 crude product of compound in chloromethanes, chloroform or ethyl acetate, through water, satisfies
And brine It, it is spin-dried for after dry, gained residue carries out column chromatography again.
8. any compound or its pharmaceutically acceptable salt application in preparation of anti-tumor drugs in claim 1.
9. a kind of pharmaceutical composition, containing any compound in the claim 1 for treating upper effective dose or its can pharmaceutically connect
The salt received.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910022937.1A CN109503697B (en) | 2019-01-10 | 2019-01-10 | 3- (L-phenylalanine) -pentacyclic triterpene derivative and synthesis method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910022937.1A CN109503697B (en) | 2019-01-10 | 2019-01-10 | 3- (L-phenylalanine) -pentacyclic triterpene derivative and synthesis method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109503697A true CN109503697A (en) | 2019-03-22 |
| CN109503697B CN109503697B (en) | 2021-08-31 |
Family
ID=65757519
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910022937.1A Expired - Fee Related CN109503697B (en) | 2019-01-10 | 2019-01-10 | 3- (L-phenylalanine) -pentacyclic triterpene derivative and synthesis method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109503697B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111635449A (en) * | 2020-07-09 | 2020-09-08 | 广州市番禺区中心医院 | Lupeol pyridine quaternary ammonium salt derivative and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101337984A (en) * | 2008-08-13 | 2009-01-07 | 中国药科大学 | Bearberry type pentacyclic triterpenes amino acid derivates, method for preparing same and pharmaceutical use thereof |
| CN101580530A (en) * | 2008-05-14 | 2009-11-18 | 北京美倍他药物研究有限公司 | Amino acid conjugate prodrug of pentacyclic triterpenoid and medical application thereof |
-
2019
- 2019-01-10 CN CN201910022937.1A patent/CN109503697B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101580530A (en) * | 2008-05-14 | 2009-11-18 | 北京美倍他药物研究有限公司 | Amino acid conjugate prodrug of pentacyclic triterpenoid and medical application thereof |
| CN101337984A (en) * | 2008-08-13 | 2009-01-07 | 中国药科大学 | Bearberry type pentacyclic triterpenes amino acid derivates, method for preparing same and pharmaceutical use thereof |
Non-Patent Citations (4)
| Title |
|---|
| REN´E CSUK等: "Synthesis and Cytotoxic Activity of Methyl Glycyrrhetinate Esterified with Amino Acids", 《ZEITSCHRIFT FÜR NATURFORSCHUNG》 * |
| STEFAN SCHWARZ等: "Synthesis and antitumor activity of glycyrrhetinic acid derivatives", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| 叶因涛等: "氨基酸类衍生物抗肿瘤作用的研究进展", 《2011年中国药学大会第11届中国药师周论文集》 * |
| 唐初等: "齐墩果酸的结构修饰与生物活性研究进展", 《CHIN.J.ORG.CHEM》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111635449A (en) * | 2020-07-09 | 2020-09-08 | 广州市番禺区中心医院 | Lupeol pyridine quaternary ammonium salt derivative and preparation method and application thereof |
| CN111635449B (en) * | 2020-07-09 | 2021-04-23 | 广州市番禺区中心医院 | Lupeol pyridine quaternary ammonium salt derivative and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109503697B (en) | 2021-08-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109575099A (en) | Dammarane saponins member derivative and its preparation method and application | |
| CN106632379B (en) | A kind of Bergenin azepine cinnamate derivative compound and its synthetic method having anti-tumor activity | |
| CN106866572B (en) | Nitric oxide donator type β elemene derivatives and its production and use | |
| CN110028547A (en) | A kind of diosgenin 3-OH derivative and preparation method thereof and medical usage | |
| CN110003304A (en) | A kind of water solubility triptolide derivative and its preparation method and application | |
| CN109503697A (en) | 3- (L-phenylalanine)-pentacyclic triterpene derivative and its synthetic method and application | |
| CN111440105B (en) | Alfacalcidol carbamate derivative and preparation method and application thereof | |
| TW201335177A (en) | Sterol derivatives and preparation method and use thereof | |
| CN110117307B (en) | Aralia saponin derivative and preparation method and application thereof | |
| CN106046105A (en) | Preparation method and application of glycyrrhetinic acid, ferulic acid and selenomethionine ternary compound | |
| CN115073406B (en) | Eucalyptus type sesquiterpene lactone TBA derivative and application thereof | |
| CN115057839B (en) | Eucalyptus type sesquiterpene lactone compound and preparation and application thereof | |
| CN105949139B (en) | A kind of sec-butyl diphenyl tetrazine benzamide compound and preparation and application | |
| CN110041239B (en) | N- (benzoyl) -L-cysteine methyl ester derivative and preparation method and application thereof | |
| CN108727403B (en) | Nodosin derivative and preparation method and application thereof | |
| TWI518094B (en) | One kind of derivatives of sterols, their preparation and use | |
| CN109517025B (en) | 28- (L-phenylalanine) -pentacyclic triterpene derivative and synthesis method and application thereof | |
| CN114853710B (en) | Gu Nazhi derivative, and preparation method, pharmaceutical composition and application thereof | |
| CN102838652B (en) | A kind of oleanolic acid derivate with anticarcinogenesis and its production and use | |
| CN113402578B (en) | Diosgenin derivative and preparation method and medical application thereof | |
| CN108864130A (en) | Enmein derivative and its preparation method and application | |
| CN113171467B (en) | Chimeric molecule based on NQO1 regulation and control and application thereof | |
| CN101993373A (en) | Chlorinated glaucocalyxin A derivative and preparation method and application thereof | |
| CN109517026B (en) | L-phenylalanine modified maslinic acid and synthetic method and application thereof | |
| CN111635395B (en) | Spirolactone type diterpene derivative, preparation method and anti-tumor application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20210831 Termination date: 20220110 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |