CN106543193B - 3- (- 4 picoline of 3- acetyl group)-(Z) -5- ethylidene -8- hydroxyls -3,4,5,6- tetra- hydrogen-based -1H- pyrans simultaneously [3,4, c]-pyridine -1- ketone and preparation method thereof - Google Patents
3- (- 4 picoline of 3- acetyl group)-(Z) -5- ethylidene -8- hydroxyls -3,4,5,6- tetra- hydrogen-based -1H- pyrans simultaneously [3,4, c]-pyridine -1- ketone and preparation method thereof Download PDFInfo
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- CN106543193B CN106543193B CN201611000013.4A CN201611000013A CN106543193B CN 106543193 B CN106543193 B CN 106543193B CN 201611000013 A CN201611000013 A CN 201611000013A CN 106543193 B CN106543193 B CN 106543193B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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Abstract
The invention belongs to chemical fields, disclose noval chemical compound 3 (3 acetyl 4 picoline) NHHP, have the function of notable anti-liver cancer and anti-, and preparation method is simple, is easy to promote the use of, and have very wide application prospect.
Description
Technical field
The invention belongs to chemical field, it is related to a kind of compound and preparation method thereof.
Technical background
Liver cancer is one of China's common cancer, and the median age of China's hepatocarcinoma patient is 40-50 Sui, and male compares women
It is common.China's liver cancer annual death rate accounts for the second of tumor mortality rate, and row third position, is only second in alimentary system malignant tumour
Stomach and the cancer of the esophagus.The drug with antitumaous effect is developed to be of great significance.
Invention content
The improving eyesight of this hair is to disclose a kind of compound with resisting liver cancer activity, and HepG2 cells can significantly be inhibited to give birth to
Long effect.It is specific as follows：
The compounds of this invention 3- (- 4 picoline of 3- acetyl group)-NHHP structures are as follows：
NHHP is Z) -5-Ethylidene-8-hydroxy-3,4,5,6,7,8-hexahydro-1H-pyrano [3,4-
c]pyridine-1-one。
The invention further relates to the preparation methods of 3- (- 4 picoline of 3- acetyl group)-NHHP：
Route is as follows：
3- hydroxyl -4- bromomethyl pyridines are synthesized by 3- hydroxy-4-methyl pyridinium tribromides
It is specific as follows：
1) 3- hydroxyl -4- bromomethyl pyridines are synthesized
It uses nitrogen to drive away air in advance in reaction bulb, CCl is added4300ml, 3- hydroxy-4-methyl pyridine 1g and azo
Bis-isobutyronitrile (AIBN) 165mg, several times be added N- bromo-succinimides (NBS) 1.64g and, 65 DEG C reflux 48h.
2) 3- (- 4 picoline of 3- hydroxyls)-NHHP is synthesized
Reaction system contains 1g (5Z) -5-ethylidene-8-hydroxy-3,4,5,6,7,8-hexahydro-
1Hpyrano[ 3,4-c]pyridin-1-one(NHHP)、700mg K2CO3, 1.9g 3- hydroxyl -4- bromomethyl pyridines, with
Methanol is solvent, reacts 72h in 60 DEG C.
3) 3- (- 4 picoline of 3- acetyl group)-NHHP is synthesized
Using tetrahydrofuran as solvent, addition molecule screening A5 is several, immobilized lipase (Novi's letter 435) several, 1g
NHHP, 2.8g vinyl acetate, 50 DEG C of reaction 72h.
4) it detaches
All product separation be all made of preparative liquid chromatography (contain 2489 UV detector of Waters, one
Waters collectors and a 250 × 10mm, 3-5 μm, ODS reverse-phase chromatographic columns), flow velocity 5ml/min, Detection wavelength is
254nm.It is 37% acetonitrile to detach all mobile phases of 3- hydroxyl -4- bromomethyl pyridines, detaches 3- (- 4 methyl pyrroles of 3- hydroxyls
Pyridine)-NHHP mobile phase be 55% methanol, separation 3- (- 4 picoline of 3- acetyl group)-NHHP mobile phase be 37% acetonitrile.
Receiving liquid merges, concentrates and be freeze-dried to obtain 3- (- 4 picoline of 3- acetyl group)-NHHP.
The invention further relates to compound 3- (- 4 picoline of 3- acetyl group)-NHHP answering in preparing medicines resistant to liver cancer
With.
NHHP is the alkaloid compound for having protect liver and hepatitis virus resisting activity, research shows that it, which does not have, inhibits liver
The activity of cancer cell HepG2 growths.Structure activity study shows that the 9-NH of NHHP is main active group, by 9-NH
Structural modification is carried out, pyridines group is introduced, can screen and obtain guide's chemical combination with HepG2 cells growth activities are significantly inhibited
Object.3- (- 4 picoline of 3- acetyl group)-NHHP that this patent the method synthesizes has significant inhibition HepG2 cells
The activity of growth can become a novel medicines resistant to liver cancer.
Beneficial effects of the present invention：The invention discloses a kind of completely new compound 3- (- 4 picoline of 3- hydroxyls)-
NHHP has antihepatocarcinoma effect.It has the significant growth for inhibiting HepG2 cells, has good application prospect.
Description of the drawings
Fig. 1 for 24 hours when NHHP, 3- (- 4 picoline of the 3- acetyl group) influences of-NHHP to HepG2 cell growths.
NHHP, 3- (- 4 picoline of the 3- acetyl group) influences of-NHHP to HepG2 cell growths when Fig. 2 48h.
Specific implementation mode
Embodiment 1
1, the synthesis of NHHP
NHHP is synthesized as follows：
1. the dry rhizome of 10kg mussot swertia herbs is shredded, ground, 40L n-butanols are added and impregnate for 24 hours, filtration drying is dense
Contract to obtain mussot swertia herb medicinal extract.
2. mussot swertia herb medicinal extract methanol dissolves, filtering takes supernatant, is eluted on 160-200 mesh silicagel columns, and elution is molten
Agent is acetate-methanol system, by ethyl acetate:Methanol=20:1, ethyl acetate:Methanol=15:1 and ethyl acetate:First
Alcohol=12:1 sequentially eluting collects ethyl acetate:Methanol=12:1 eluent, is concentrated to give concentrate, micro- using 0.25 μm
Hole membrane filtration obtains filtering with microporous membrane liquid.
3. 10g carrots, 10g potatoes, chopping are added 500ml distilled water and boil 20min, filter, the Portugals 8g are added in filtrate
Grape sugar, is diluted to 1000ml with distilled water, obtains PDA liquid medium；5ml sterile waters move into aspergillus niger inclined-plane, shake, and draw
In the PDA liquid medium of 2ml solution access sterilizing, 28 DEG C, 160rpm is cultivated for 24 hours；
4. will 2. gained 0.25 μm of filtering with microporous membrane of concentrate, filtrate is with volume ratio 8:3. gained is added in 100 ratios
Fermentation of Aspergillus niger liquid in, cultivate 5d under 28 DEG C, the condition of culture of 160rpm.Zymotic fluid is collected, filtering takes fermentation to filter
Liquid.
5. the chloroform of 2 times of volumes of the fermentation filtrate of 4. gained is extracted 3 times, merging filtrate is concentrated under reduced pressure and removes dechlorination
It imitates and dries, using HPD-300 types, water and 15% ethanol elution, flow velocity 1BV/h is respectively adopted in macroreticular resin post separation；15%
Ethanol elution concentrated liquor uses 160-200 mesh silicagel column elutions, and chloroform is respectively adopted：Methanol=7:1, chloroform：Methanol=6:
1, chloroform：Methanol=5:1 and chloroform：Methanol=4:1 elution collects chloroform：Methanol=4:1 eluent is simultaneously dense
Contracting, concentrate are further purified using preparative liquid chromatography again, and the mobile phase of preparative liquid chromatography is 10% acetonitrile；Collect outflow
Liquid, concentration are freeze-dried up to up to NHHP.
2,3- hydroxyl -4- bromomethyl pyridines are synthesized
It uses nitrogen to drive away air in advance in reaction bulb, CCl is added4300ml, 3- hydroxy-4-methyl pyridine 1g and azo
Bis-isobutyronitrile (AIBN) 165mg, several times be added N- bromo-succinimides (NBS) 1.64g and, 65 DEG C reflux 48h.
3,3- (- 4 picoline of 3- hydroxyls)-NHHP is synthesized
Reaction system contains 1g (5Z) -5-ethylidene-8-hydroxy-3,4,5,6,7,8-hexahydro-
1Hpyrano[ 3,4-c]pyridin-1-one(NHHP)、700mg K2CO3, 1.9g 3- hydroxyl -4- bromomethyl pyridines, with
Methanol is solvent, reacts 72h in 60 DEG C.
4,3- (- 4 picoline of 3- acetyl group)-NHHP is synthesized
Using tetrahydrofuran as solvent, molecular sieve-4 A 5 (lark prestige Science and Technology Ltd.) 20g, immobilized lipase (promise is added
Dimension believes 435) 5g, 1g NHHP, 2.8g vinyl acetates, 50 DEG C of reaction 72h.
5, it detaches
All product separation be all made of preparative liquid chromatography (contain 2489 UV detector of Waters, one
Waters collectors and a 250 × 10mm, 3-5 μm, ODS reverse-phase chromatographic columns), flow velocity 5ml/min, Detection wavelength is
254nm.It is 37% acetonitrile to detach all mobile phases of 3- hydroxyl -4- bromomethyl pyridines, detaches 3- (- 4 methyl pyrroles of 3- hydroxyls
Pyridine)-NHHP mobile phase be 55% methanol, separation 3- (- 4 picoline of 3- acetyl group)-NHHP mobile phase be 37% acetonitrile.
Receiving liquid merges, concentrates and be freeze-dried to obtain 3- (- 4 picoline of 3- acetyl group)-NHHP.
The structured data of product：
White needles, m.p.125-147 DEG C, IR (CHCl3) vmax：3480,1670,1625,1450,1480cm-1,1H
NMR (400MHz, CDCl3)δ：6.38 (1H, s, H-2), 6.79 (1H, dd, J=17.6,11.2Hz, H-4), 3.09 (2H, t, J
=6.0, H-6), 4.57 (2H, t, J=6.0, H-7), 5.59 (1H, dd, J=0.7,17.6, H-7a), 7.45 (1H, s, H-
10), 3.12 (3H, J=8.4 .5,7.6, H-11), 4.7 (1H, H-12), 6.8 (1H, H-14), 8.5 (1H, H-15), 7.9
(1H, H-16), 2.1 (3H, J=8.5,3.5,7.6).13C NMR (400MHz, CDCl3)δ：163.9 (C-1), 151.3 (C-
2), 127.8 (C-4), 132.6 (C-5), 24.2 (C-6), 87.6 (C-7), 121.5 (C-8), 141.0 (C-9), 150.7 (C-
10), 18.9 (C-11), 61.5 (C-12), 135.6 (C-13), 123.1 (C-14), 145.8 (C-15), 144.2 (C-17),
146.8 (C-18), 169.4 (C-19), 22.3 (C-20).
2 3- of embodiment (- 4 picoline of 3- acetyl group)-NHHP antihepatocarcinoma effects
The culture medium of HepG2 cells is that DMEM culture mediums are, and 2mM Pidolidones, 20U/ml penicillin, 20 μ g/ are added
The bovine serum albumin of ml streptomysins and 10% heat inactivation, in 37 DEG C, 5%CO2Under conditions of cultivate 72h, then with 0.025%
Trypsin solution is by cell blood at suspended state.By HepG2 cell inoculations in 96 orifice plates, continue to train under the same conditions
It supports for 24 hours, is then separately added into 15.6,31.3,62.5,125,250 and 500 μ g/ml NHHP and 3- (- 4 methyl pyrroles of 3- acetyl group
Pyridine)-NHHP solution, using blank cultures as negative control.Continue to measure OD after cultivating 24 and 48h570And inhibiting rate is calculated, press down
Rate processed is calculated using following formula：Inhibiting rate (%)=(1-ODSun/ODIt is cloudy) × 100%.
As a result：
See that Fig. 1,3- (- 4 picoline of 3- acetyl group)-NHHP have the significant activity for inhibiting HepG2 cell growths,
24, when 48h, 3- (- 4 picoline of 3- acetyl group)-NHHP of 192 μ g/ml respectively reaches the inhibiting rate of HepG2 cell growths
83.4% and 95.1%, noticeably greater than (P<0.01) (inhibiting rate of NHHP is respectively 38.5% He to the inhibiting rate of NHHP
44.3%).The IC of 3- (- 4 picoline of 3- acetyl group)-NHHP when 48h50For 18.5 μ g/ml.
It can be seen that the compounds of this invention 3- (- 4 picoline of 3- acetyl group)-NHHP is with significant antihepatocarcinoma effect.
Embodiment 3
1 gained 3- of embodiment (- 4 picoline of 3- acetyl group)-NHHP is added into conventional medicine component, conventional agent is made
Type such as tablet, electuary etc..
Claims (3)
1. a kind of compound 3- (- 4 picoline of 3- acetyl group)-(Z) -5- ethylidene -8- hydroxyls -3,4,5,6- tetra- hydrogen-based -1H-
Simultaneously [3,4, c]-pyridine -1- ketone, structural formula are as follows for pyrans：
2. compound 3- described in claim 1 (- 4 picoline of 3- acetyl group)-(Z) -5- ethylidene -8- hydroxyls -3,4,5,6-
The preparation method of four hydrogen-based -1H- pyrans simultaneously [3,4, c]-pyridine -1- ketone, it is characterised in that：Steps are as follows：
1) (Z) -5- ethylidene -8- hydroxyls -3,4, the preparation of 5,6- tetra- hydrogen-based -1H- pyrans simultaneously [3,4, c]-pyridine -1- ketone：
1. the dry rhizome of 10kg mussot swertia herbs is shredded, ground, 40L n-butanols are added and impregnate for 24 hours, filtration drying is concentrated to give
Mussot swertia herb medicinal extract；
2. mussot swertia herb medicinal extract is dissolved with methanol, filtering takes supernatant, is eluted on 160-200 mesh silicagel columns, eluting solvent
For acetate-methanol system, by ethyl acetate：Methanol=20:1, ethyl acetate：Methanol=15:1 and ethyl acetate：Methanol
=12:1 sequentially eluting collects ethyl acetate：Methanol=12:1 eluent, is concentrated to give concentrate, is filtered using 0.25 μm of micropore
Membrane filtration obtains filtering with microporous membrane liquid；
3. 10g carrots, 10g potatoes, chopping are added 500ml distilled water and boil 20min, filter, 8g glucose is added in filtrate,
It is diluted to 1000ml with distilled water, obtains PDA liquid medium；5ml sterile waters move into aspergillus niger inclined-plane, and it is molten to draw 2ml for concussion
In the PDA liquid medium of liquid access sterilizing, 28 DEG C, 160rpm is cultivated for 24 hours；
4. will 2. gained miillpore filter filtrate with volume ratio 8:100 ratio is added in the 3. fermentation of Aspergillus niger liquid of gained, 28
DEG C, continue to cultivate 5d under the condition of culture of 160rpm；Zymotic fluid is collected, filtering takes fermentation filtrate；
5. the chloroform of 2 times of volumes of the fermentation filtrate of 4. gained is extracted 3 times, merging filtrate is concentrated under reduced pressure and removes chloroform simultaneously
Dry, using HPD-300 types, water and 15% ethanol elution, flow velocity 1BV/h is respectively adopted in macroreticular resin post separation；15% ethyl alcohol
It elutes concentrated liquor and uses 160-200 mesh silicagel column elutions, chloroform is respectively adopted：Methanol=7:1, chloroform：Methanol=6:1, chlorine
It is imitative：Methanol=5:1 and chloroform：Methanol=4:1 elution collects chloroform：Methanol=4:1 eluent and concentration, it is dense
Contracting liquid is further purified using preparative liquid chromatography again, and the mobile phase of preparative liquid chromatography is 10% acetonitrile；Collect efflux, dense
It contracts, be freeze-dried up to (Z) -5- ethylidene -8- hydroxyls -3,4,5,6- tetra- hydrogen-based -1H- pyrans simultaneously [3,4, c]-pyridine -1- ketone；
2) 3- hydroxyl -4- bromomethyl pyridines are synthesized
It uses nitrogen to remove air in advance in reaction bulb, CCl is added4Two isobutyl of 300ml, 3- hydroxy-4-methyl pyridine 1g and azo
Nitrile 165mg, several times be added N- bromo-succinimides 1.64g and, 65 DEG C reflux 48h；
3) synthesis 3- (- 4 picoline of 3- acetyl group)-(Z) -5- ethylidene -8- hydroxyls -3,4,5,6- tetra- hydrogen-based -1H- pyrans are simultaneously
[3,4, c]-pyridine -1- ketone
Reaction system ethylidene -8- hydroxyls -3,4 containing 1g (Z) -5-, 5,6- tetra- hydrogen-based -1H- pyrans simultaneously [3,4, c]-pyridine -1-
Ketone, 700mgK2CO3,1.9g3- hydroxyl -4- bromomethyl pyridines react 72h using methanol as solvent in 60 DEG C；
4) synthesis 3- (- 4 picoline of 3- acetyl group)-(Z) -5- ethylidene -8- hydroxyls -3,4,5,6- tetra- hydrogen-based -1H- pyrans are simultaneously
[3,4, c]-pyridine -1- ketone
Using tetrahydrofuran as solvent, molecule is added and screens A510g, immobilized lipase 5g, 1g (Z) -5- ethylidene -8- hydroxyls -
3,4,5,6- tetra- hydrogen-based -1H- pyrans simultaneously [3,4, c]-pyridine -1- ketone, 2.8g vinyl acetates, 50 DEG C of reaction 72h；
5) separation method
All product separation are all made of Waters preparative liquid chromatographs；It is all to detach 3- hydroxyl -4- bromomethyl pyridines
Mobile phase is 37% acetonitrile, separation 3- (- 4 picoline of 3- hydroxyls)-(Z) -5- ethylidene -8- hydroxyls -3,4,5,6- tetra- hydrogen-baseds -
The mobile phase of 1H- pyrans simultaneously [3,4, c]-pyridine -1- ketone is 55% methanol, separation 3- (- 4 picoline of 3- acetyl group)-(Z) -
5- ethylidene -8- hydroxyls -3,4, simultaneously [3,4, c]-pyridine -1- ketone mobile phases are 37% acetonitrile to 5,6- tetra- hydrogen-based -1H- pyrans；It connects
It receives liquid merging, concentrate and be freeze-dried to obtain 3- (- 4 picoline of 3- acetyl group)-(Z) -5- ethylidene -8- hydroxyls -3,4,5,6-
Four hydrogen-based -1H- pyrans simultaneously [3,4, c]-pyridine -1- ketone.
3. compound 3- described in claim 1 (- 4 picoline of 3- acetyl group)-(Z) -5- ethylidene -8- hydroxyls -3,4,5,6-
Simultaneously application of [3,4, c]-pyridine -1- ketone in preparing medicines resistant to liver cancer of four hydrogen-based -1H- pyrans.
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