CN108864089A - A kind of new indole and pyridone drug molecule and its preparation method and application - Google Patents
A kind of new indole and pyridone drug molecule and its preparation method and application Download PDFInfo
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- AJKVCIJGEHNDTH-UHFFFAOYSA-N CCCCc1c(CC)cccc1C(c([nH]c1c2c(Cl)cc(Cl)c1)c2N1)=CC1=O Chemical compound CCCCc1c(CC)cccc1C(c([nH]c1c2c(Cl)cc(Cl)c1)c2N1)=CC1=O AJKVCIJGEHNDTH-UHFFFAOYSA-N 0.000 description 1
- LQVOQILOHJTNPO-UHFFFAOYSA-N CCOC(c([nH]c1cc(Cl)cc(Cl)c11)c1N)=O Chemical compound CCOC(c([nH]c1cc(Cl)cc(Cl)c11)c1N)=O LQVOQILOHJTNPO-UHFFFAOYSA-N 0.000 description 1
- 0 CCOC(c1c(*)c(c(Cl)cc(Cl)c2)c2[n]1)=O Chemical compound CCOC(c1c(*)c(c(Cl)cc(Cl)c2)c2[n]1)=O 0.000 description 1
- HORCMGDYJBZPQW-UHFFFAOYSA-N O=C(C=C1c2cccc3c2cccn3)Nc2c1[nH]c1c2c(Cl)cc(Cl)c1 Chemical compound O=C(C=C1c2cccc3c2cccn3)Nc2c1[nH]c1c2c(Cl)cc(Cl)c1 HORCMGDYJBZPQW-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a kind of new indole and pyridone drug molecules and its preparation method and application, belong to medical synthesis technical field.Technical solution of the present invention main points are：A kind of new indole and pyridone drug molecule, structural formula are：
Description
Technical field
The invention belongs to medical synthesis technical fields, and in particular to a kind of new indole and pyridone drug molecule and its system
Preparation Method and application.
Background technique
Hexa-atomic nitrogen-containing heterocycle compound is the skeleton part of many pharmaceutical activity molecules.Much containing pyridine, pyridone and
The molecule of the skeletons such as dihydropyridone all shows good pharmacological activity, such as Nothapodytine B and Nothapodytine
A is the compound separated from foetid nothapodytes herb, pharmacological evaluation proves that it has a fine antiviral activity, and they spread out
Biological Mappicine and Camptothecin is then the inhibitor of the topoisomerase I of DNA, has certain anti-tumor activity,
Compound Streptonigrone is separated from the culture solution of streptomyces, and good anti-tumor activity is shown.
Lycoricidine, Narciclasine and Pancratistatin are isolated one kind biologies from narcissus platymiscium
Alkali all has good bioactivity, such as the anti-food activity of insect, anti-tumor activity.
Trypoline class compound is the structure parent nucleus and important intermediate of many natural products, they have anti-mistake
Quick, anti-inflammatory, antitumor, potent town is logical and the physiological activity such as bring down a fever.Existing much relevant reports about such compound activity,
Be mostly by indole ring nitrogen and pyridine ring modify, so that it may obtain the compound with different physiological activity.
Cloud density in indoles substance on pyrrole ring is relatively high, is easier to be chemically reacted, therefore indoles and its derivative
Object is the important skeleton of natural products, and is the important skeleton of pharmaceutical activity molecule, thus the functional group on indole ring always with
All to be studied by the personnel of organic synthesis field very much.Indoles and its derivative are also used as heterocycle Alkaloid, it is most of all
With significant medical value and physiological activity.In new drug development, indole structure is often prioritized as lead compound
And studied, such as using 5- methoxyindole-3-carboxaldehyde and thiocarbohydrazide as Material synthesis (thiosemicarbazone)
Schiff compound.Indoles and its derivative can synthesize antipyretic-antalgic agent, excitant, depressor, vasodilator agent, anti-group
The drug of amine medicine etc..Recently, compound of the research discovery containing indole structure skeleton of field of biomedicine is to certain kinases
Expression has certain inhibiting effect, has potential anti-tumor activity and good clinical development prospect, potential to apply
Value attracts people and has carried out a large amount of exploration to its route of synthesis, such as each single function enzyme of bacterial fatty acid enzyme system
Have become the research hotspot of novel antibacterial drug targets of genomics driving, novel 2- indole ketone c-Met kinase inhibitor
Design；The building of carrier indocyanine green and Doxorubicin self-assembled micelle；Bis- (1H-2- indyl) ketones are as a kind of novel
Platinum family growth factor receptor kinase inhibitor；2-aroylindole derivative is synthesized as a kind of new effective tubulose suppression
System, antibiont drug；2-Aroylindoles and 2- acyl group benzene carbamide compounds n- hydroxypropyl acrylamide substructure is as a combination
Manage the histone deacetylase inhibitor of design；The excellent antitumor activity of 2,4- diaminopyrimidine derivatives.Indoles and
Its derivative has various pharmacology and biological characteristics, including：Antibacterial, cytotoxicity, anti-oxidant and insecticidal activity are such as made
The process of standby photolytic activity oxygen trazodone derivative.
Summary of the invention
Simple, low in raw material price that the technical problem to be solved by the present invention is to provide a kind of synthetic methods, structure novel
The preparation method and application of trypoline ketone drug molecule.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of trypoline ketone drug molecular structure
For：Wherein R is to fluorobenzene, quinoline and indoles.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of system of trypoline ketone drug molecule
Preparation Method, it is characterised in that the specific steps are：
A, 3,5- dichloroaniline is added in the mixed solution of water and sulfuric acid, 0 DEG C is cooled to after mixing evenly, in stirring bar
Under part, the aqueous solution dissolved with sodium nitrite is added dropwise, carries out diazo-reaction and obtains solution A；Match in another reaction flask
The aqueous solution dissolved with barium hydroxide is set, under the conditions of 0 DEG C, the ethyl alcohol dissolved with ethyl pyruvate is slowly added dropwise, is stirred after dripping
It mixes uniformly to prepare and obtains solution B；Solution A as under the conditions of 0 DEG C, solution B is added dropwise to solution A by slow obtain, and is risen after dripping
The condensation reaction of amine aldehyde, filtering reacting liquid occur for temperature to 40 DEG C of reaction a period of times, then extract filtrate with ether, after merging organic phase
It is dry with anhydrous magnesium sulfate, ethyl -2- (2- (3,5- dichloro-benzenes are recrystallized to give through n-hexane and acetone mixed solution after concentration
Base) hydrazono-) propionic acid；The volume ratio of the n-hexane and acetone is 2:1.
B, ethyl -2- (2- (3,5- dichlorophenyl) hydrazono-) propionic acid and polyphosphoric acids are added in toluene, heat 45 DEG C,
Vacuum is opened after being stirred to react a period of time, divides exactly toluene, ice water is then added, filters reaction solution, filter cake warp after mixing evenly
N-hexane is recrystallized to give 4,6- dichloro-indole Ethyl formate.
C, 4,6- dichloro-indole Ethyl formate, sodium nitrite, potassium peroxydisulfate are added to formic acid, continued under the conditions of 90 DEG C
It is stirred to react to raw material fully reacting, is subsequently poured into water, it is multiple to be extracted with ethyl acetate reaction solution, uses nothing after merging organic phase
Aqueous sodium persulfate is dry, through isolated 2- nitro -4, the 6- dichloro-indole Ethyl formate of silica gel column chromatography after concentration of reaction solution.
D, 2- nitro -4,6- dichloro-indole Ethyl formate and catalyst palladium carbon are added in methanol, are passed through in autoclave
Hydrogen, pressure reach 0.2MPa, and reaction temperature is 40 DEG C, reaction to raw material fully reacting, filtering reacting liquid, and filtrate is concentrated to get
Pure 2- amido -4,6- dichloro-indole Ethyl formate.
E, by 2- amido -4,6- dichloro-indole Ethyl formate adding into dichloromethane, triethylamine is added, is cooled to 10
DEG C, 4- chloroformyl ethyl acetate is slowly added dropwise, overnight, TLC monitors raw material fully reacting for room temperature reaction, and it is dilute to add methylene chloride
Reaction solution is released, twice, anhydrous sodium sulfate is dry for washing, is spin-dried for both obtaining 2- formamido ethyl acetate -4,6- dichloro-indole formic acid
Ethyl ester.
F, 2- formamido ethyl acetate -4,6- dichloro-indole Ethyl formate is added in tetrahydrofuran, then added in batches
Enter potassium tert-butoxide, reaction temperature control is added ice water after less than 25 DEG C, reacting a period of time and is quenched, with the HCl tune of 2mol/L
Saving reaction solution pH is 3, and filtering, vacuum drying obtains off-white powder product 7, bis- chloro-4-hydroxyl -2- carbonyl -2,5- dihydro of 9- -
1H- pyrido [3,2-b] indole -3-carboxylic acid ethyl ester.
G, add 7,9- bis- chloro-4-hydroxyl -2- carbonyl -2,5- dihydro -1H- pyrido [3,2-b] Yin in batches in HCl solution
Diindyl -3- Ethyl formate is heated to 100 DEG C, and reaction overnight, is spin-dried for reaction dissolvent, then washed with ether, and it is white that vacuum drying obtains class
Color solid 7,9- bis- chloro-4-hydroxyl -2- carbonyl -2,5- dihydro -1H- pyrido [3,2-b] indoles.
H, in closed reaction flask, 7,9-, bis- chloro-4-hydroxyl -2- carbonyl -2,5- bis- is added portionwise into phosphorus oxychloride
Hydrogen -1H- pyrido [3,2-b] indoles is slowly heated to 100 DEG C, and overnight, after TLC monitors raw material fully reacting, vacuum is revolved for reaction
Dry phosphorus oxychloride obtains the ethyl acetate that 10 times of volumes are added in Red oil concentrate, and washing three times, separates organic phase, then use chlorine
Change sodium solution washing, dry, rotation reaction solution obtains chloro- 2- carbonyl -2, the 5- dihydro -1H- pyrido [3,2-b] of the chloro- 4- of 7,9- bis-
Indoles.
I, chloro- 2- carbonyl -2,5- dihydro -1H- pyrido [3,2-b] indoles of the chloro- 4- of 7,9- bis- is added to tetrahydrofuran
In, potassium phosphate and boronic acid derivatives are added, is heated to 100 DEG C, is added after concentration is extracted with ethyl acetate after reaction a period of time
Enter into methanol and dilute hydrochloric acid and Isosorbide-5-Nitrae-dioxane mixed solution, room temperature reaction to raw material fully reacting, vacuum concentration, ether
Washing, obtains
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of system of trypoline ketone drug molecule
Preparation Method, it is characterised in that the specific steps are：
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
In reaction flask, 3,5- dichloroaniline 48g (0.3mol) is added the mixed solution of water 500mL and hydrochloric acid 500mL
In, it is cooled to 0 DEG C after mixing evenly, under agitation, the aqueous solution dissolved with sodium nitrite 23g (0.34mol) is added dropwise
400mL is uniformly mixed after dripping and obtains solution A；Configuration is dissolved with potassium hydroxide 67g's (1.2mol) in another reaction flask
The ethyl alcohol 250mL dissolved with ethyl pyruvate 35g (0.3mol) is slowly added dropwise under the conditions of 0 DEG C in aqueous solution 1000mL, is added dropwise
Preparation is stirred evenly after complete obtains solution B；Solution A as under the conditions of 0 DEG C, solution B is added dropwise to solution A by slow obtain, and is added dropwise
It is warming up to 40 DEG C of reaction 10min after complete, then three times with ether 1000mL extraction reaction solution, uses anhydrous magnesium sulfate after merging organic phase
100g is dry, through n-hexane and acetone mixed solution (V after concentrationN-hexane：VAcetone=2:1) it is recrystallized to give ethyl -2- (2- (3,5-
Dichlorophenyl) hydrazono-) propionic acid 78g, yield 95%；1H NMR(600MHz,DMSO-d6):δ10.08(s,1H),7.23(d,
J=6.0Hz, 2H), 7.03 (d, J=6.0Hz, 1H), 4.22 (q, J=12.0Hz, 2H), 2.07 (s, 3H), 1.28 (t, J=
12.0Hz,3H)；13C NMR(150MHz,DMSO-d6):δ164.66,146.98,135.32,134.79,119.75,112.16,
61.06,14.39,12.33。
Embodiment 2
In reaction flask, ethyl -2- (2- (3,5- dichlorophenyl) hydrazono-) propionic acid 80g (0.29mol) and poly phosphorus
Sour 500g (1.47mol) is added in toluene 1000mL, heats 45 DEG C, opens vacuum after being stirred to react 1h, divide exactly toluene, then plus
Enter ice water 2000mL, filters reaction solution after stirring 10min, filter cake is recrystallized to give 4,6- dichloro-indole Ethyl formate through n-hexane
66g, yield 89%；1H NMR(600MHz,DMSO-d6):δ12.41(s,1H),7.46(s,1H),7.28(s,1H),7.12
(s,1H),4.37(dd,J1=6.0Hz, J2=6.0Hz, 2H), 1.35 (t, J1=6.0Hz, J2=6.0Hz, 3H)13C NMR
(150MHz,DMSO-d6):δ161.03,138.04,129.54,129.20,127.34,124.82,120.51,111.84,
105.78,61.44,14.66。
Embodiment 3
In reaction flask, 4,6- dichloro-indole Ethyl formate 26g (0.1mol), sodium nitrite 28g (0.4mol), over cure
Sour potassium 100g (0.4mol) is added in formic acid 500mL, continues to be stirred to react 2h under the conditions of 90 DEG C, TLC monitors raw material reaction
Completely, it is subsequently poured into water 600mL, three times with ethyl acetate 300mL extraction reaction solution, uses anhydrous sodium sulfate after merging organic phase
It is dry, (V petroleum ether is separated through silica gel column chromatography after concentration of reaction solution：V ethyl acetate is 4:1) 2- nitro -4,6- dichloro is obtained
Indolecarboxylic acid ethyl ester 28.5g, yield 95%；1H NMR(600MHz,DMSO-d6):δ12.15(s,1H),7.59(s,1H),
7.04-7.03 (m, 1H), 4.37 (d, J=6.0Hz, 2H), 1.28-1.27 (m, 3H).
Embodiment 4
In 500mL reaction flask, 2- nitro -4,6- dichloro-indole Ethyl formate 30g (0.1mol) and catalyst palladium carbon
3g is added in 200mL methanol, and hydrogen is passed through in autoclave, and pressure reaches 0.2MPa, and reaction temperature is 40 DEG C, after reacting 12h
Raw material fully reacting, filtering reacting liquid are monitored through TLC, filtrate is concentrated to get pure 2- amido -4,6- dichloro-indole formic acid second
Ester 26g, yield 96%.
Embodiment 5
In 500mL reaction flask, 2- nitro -4,6- dichloro-indole Ethyl formate 30g (0.1mol) and catalyst palladium carbon
3g is added in 200mL methanol, and hydrogen is passed through in autoclave, and pressure reaches 0.05MPa, and reaction temperature is 40 DEG C, after reacting 12h
Raw material fully reacting, filtering reacting liquid, through the isolated pure 2- amido-of silica gel column chromatography after filtrate concentration are monitored through TLC
4,6- dichloro-indole Ethyl formate 22g, yield 81%.
Embodiment 6
In 500mL reaction flask, 2- nitro -4,6- dichloro-indole Ethyl formate 30g (0.1mol) and catalyst palladium carbon
3g is added in 200mL methanol, and hydrogen is passed through in autoclave, and pressure reaches 0.1MPa, and reaction temperature is 40 DEG C, after reacting 12h
Raw material fully reacting is monitored through TLC, filtering reacting liquid obtains pure 2- amido -4,6- dichloro-indole formic acid after filtrate concentration
Ethyl ester 24g, yield 88%.
Embodiment 7
In 500mL reaction flask, 2- nitro -4,6- dichloro-indole Ethyl formate 30g (0.1mol) and catalyst palladium carbon
3g is added in 200mL methanol, and hydrogen is passed through in autoclave, and pressure reaches 0.4MPa, and reaction temperature is 40 DEG C, after reacting 12h
Raw material fully reacting, filtering reacting liquid, through the isolated pure 2- amido-of silica gel column chromatography after filtrate concentration are monitored through TLC
4,6- dichloro-indole Ethyl formate 25g, yield 92%.
Embodiment 8
In reaction flask, 2- amido -4,6- dichloro-indole Ethyl formate 27g (0.1mol) is added to methylene chloride
In 250mL, triethylamine 11g (0.11mol) is added, is cooled to 10 DEG C, 4- chloroformyl ethyl acetate 16g is slowly added dropwise
(0.105mol), overnight, TLC monitors raw material fully reacting for room temperature reaction, adds methylene chloride 250mL dilute reaction solution, water
It washes twice, anhydrous sodium sulfate is dry, is spin-dried for both obtaining 2- formamido ethyl acetate -4,6- dichloro-indole Ethyl formate 28g, yield
It is 73%；1H NMR(600MHz,DMSO-d6):δ12.11(s,1H),7.79-7.78(m,1H),7.41(s,1H),7.09(s,
1H), 4.92 (d, J=6.0Hz, 3H), 4.11 (d, J=12.0Hz, 2H), 3.35 (s, 2H), 1.29 (s, 3H).
Embodiment 9
In reaction flask, 2- formamido ethyl acetate -4,6- dichloro-indole Ethyl formate 37g (0.1mol) is added to
In THF400mL, then t-BuOK 23g (0.2mol) is added portionwise, ice is added after reacting 1h less than 25 DEG C in reaction temperature control
Water 300mL is quenched, and adjusting reaction solution pH with the HCl of 2mol/L is 3, and filtering, vacuum drying obtains off-white powder product 7,9-
Two chloro-4-hydroxyl -2- carbonyl -2,5- dihydro -1H- pyrido [3,2-b] indole -3-carboxylic acid ethyl ester 30g, yield 88%；1H
NMR(600MHz,DMSO-d6):δ15.98(s,1H),11.81(s,1H),7.66-7.65(m,1H),7.24-7.22(m,1H),
4.44 (d, J=6.0Hz, 2H), 1.26 (s, 3H).
Embodiment 10
In reaction flask, the HCl solution 200mL in 6mol/L is added, then adds 7,9-, bis- chloro-4-hydroxyl -2- carbonyl-in batches
2,5- dihydro -1H- pyrido [3,2-b] indole -3-carboxylic acid ethyl ester 34g (0.1mol) are heated to 100 DEG C, and reaction overnight, is spin-dried for
Reaction dissolvent, then washed with ether, vacuum drying obtains off-white powder 7, bis- chloro-4-hydroxyl -2- carbonyl -2,5- dihydro of 9- -
1H- pyrido [3,2-b] indoles 22g, yield 82%；–HRMS((+)-ESI):M/z=268.9735
(calcd.268.9743for C11H6Cl2N2O2,[M+H]+)。
Embodiment 11
In closed reaction flask, it is added portionwise in phosphorus oxychloride 50g (0.5mol) dissolved with 7,9-, bis- chloro-4-hydroxyl-
The toluene 150mL of 2- carbonyl -2,5- dihydro -1H- pyrido [3,2-b] indoles 27g (0.1mol), is slowly heated to 100 DEG C, instead
It should stay overnight, after TLC monitors raw material fully reacting, vacuum is spin-dried for phosphorus oxychloride and solvent toluene obtains Red oil product concentrate
The ethyl acetate of 10 times of volumes of concentrate is added, washing three times, separates organic phase, it is chloro- that drying obtains the chloro- 4- of 7,9- bis- after being spin-dried for
2- carbonyl -2,5- dihydro -1H- pyrido [3,2-b] indoles 22g, yield 77%；1H NMR(400M,CDCl3):δ12.02
(s,1H),7.68(s,1H),7.24(s,1H),6.69(s,1H)。
Embodiment 12
Chloro- 2- carbonyl -2,5- dihydro -1H- pyrido [3,2-b] the indoles 30g (0.1mol) of the chloro- 4- of 7,9- bis- is added to
In THF600mL, adds the potassium phosphate 330mL of 1mol/L and to fluorobenzoic boric acid 25g (0.12mol), be heated to 100 DEG C, reaction
It is extracted with ethyl acetate afterwards after concentration for 24 hours and is added to the HCl/1 of methanol 300mL and 12mol/L, in 4- dioxane 300mL, room
Temperature reaction 5h, TLC monitor raw material fully reacting, vacuum concentration, and ether washing obtains20g,
HPLC purity is 98.7%, yield 58%；1H NMR(400M,CDCl3):11.98(s,1H),7.77-7.76(m,2H),
7.65 (d, J=4.0Hz, 1H), 7.61 (s, 1H), 7.41-7.39 (m, 2H), 7.16 (t, J1=8.0Hz, J2=8.0Hz, 1H),
6.61(s,1H)；MS(ESI)m/z:347.7[M+H]+；Anal.Calcd for C17H9Cl2FN2O:C,58.81；H,2.61；N,
8.07.Found:C,58.67；H,2.66；N,8.14.
Embodiment 13
Chloro- 2- carbonyl -2,5- dihydro -1H- pyrido [3,2-b] the indoles 30g (0.1mol) of the chloro- 4- of 7,9- bis- is added to
In THF600mL, adds the potassium phosphate 200mL of 1mol/L and to fluorobenzoic boric acid 25g (0.12mol), be heated to 100 DEG C, reaction
It is extracted with ethyl acetate afterwards after concentration for 24 hours and is added to the HCl/1 of methanol 300mL and 12mol/L, in 4- dioxane 300mL, room
Temperature reaction 5h, TLC monitor raw material fully reacting, vacuum concentration, ether washing, silica gel column chromatography (petroleum ether after concentration：Acetic acid second
Ester=6：1) it obtains12g, HPLC purity are 99%, yield 35%；1H NMR(400M,
CDCl3):11.98 (s, 1H), 7.77-7.76 (m, 2H), 7.65 (d, J=4.0Hz, 1H), 7.61 (s, 1H), 7.41-7.39
(m,2H),7.16(t,J1=8.0Hz, J2=8.0Hz, 1H), 6.61 (s, 1H)；MS(ESI)m/z:347.7[M+H]+；
Anal.Calcd for C17H9Cl2FN2O:C,58.81；H,2.61；N,8.07.Found:C,58.67；H,2.66；N,8.14.
Embodiment 14
Chloro- 2- carbonyl -2,5- dihydro -1H- pyrido [3,2-b] the indoles 30g (0.1mol) of the chloro- 4- of 7,9- bis- is added to
In THF600mL, adds the potassium phosphate 400mL of 1mol/L and to fluorobenzoic boric acid 25g (0.12mol), be heated to 100 DEG C, reaction
It is extracted with ethyl acetate afterwards after concentration for 24 hours and is added to the HCl/1 of methanol 300mL and 12mol/L, in 4- dioxane 300mL, room
Temperature reaction 5h, TLC monitor raw material fully reacting, vacuum concentration, ether washing, silica gel column chromatography (petroleum ether after concentration：Acetic acid second
Ester=6：1) it obtains18g, HPLC purity are 99.6%, yield 52%；1H NMR(400M,
CDCl3):11.98 (s, 1H), 7.77-7.76 (m, 2H), 7.65 (d, J=4.0Hz, 1H), 7.61 (s, 1H), 7.41-7.39
(m,2H),7.16(t,J1=8.0Hz, J2=8.0Hz, 1H), 6.61 (s, 1H)；MS(ESI)m/z:347.7[M+H]+；
Anal.Calcd for C17H9Cl2FN2O:C,58.81；H,2.61；N,8.07.Found:C,58.67；H,2.66；N,8.14.
Embodiment 15
Chloro- 2- carbonyl -2,5- dihydro -1H- pyrido [3,2-b] the indoles 29g (0.1mol) of the chloro- 4- of 7,9- bis- is added to
In THF600mL, the potassium phosphate 330mL and quinoline -4- boric acid 20g (0.12mol) of 1mol/L are added, is heated to 100 DEG C, instead
It should be extracted with ethyl acetate afterwards for 24 hours after concentration and be added to the HCl/1 of methanol 400mL and 12mol/L, in 4- dioxane 400mL,
5h is reacted at room temperature, TLC monitors raw material fully reacting, vacuum concentration, and ether washing obtains
25g, HPLC purity are 98.9%, yield 66%；1H NMR(400M,CDCl3):12.39 (s, 1H), 8.32 (d, J=
8.0Hz,1H),7.91(s,2H),7.76(s,1H),7.53-7.51(m,2H),7.49-7.48(m,2H),6.97(t,J1=
12.0Hz,J2=12.0Hz, 1H), 6.54 (s, 1H), MS (ESI) m/z:380.2[M+H]+；Anal.Calcd for
C20H11Cl2N3O:C,63.18；H,2.92；N,11.05.Found:C,63.35；H,3.01；N,11.18.
Embodiment 16
Chloro- 2- carbonyl -2,5- dihydro -1H- pyrido [3,2-b] the indoles 29g (0.1mol) of the chloro- 4- of 7,9- bis- is added to
In THF 600mL, the potassium phosphate 330mL and indoles -4- boric acid 19g (0.12mol) of 1mol/L are added, is heated to 100 DEG C, instead
Answer the HCl/1,4- dioxy six that methanol 400mL and 12mol/L are added to after being concentrated three times after 15h with ethyl acetate 400mL extraction
In ring 400mL, 3h is reacted at room temperature, TLC monitors raw material fully reacting, vacuum concentration, and ether washing obtains28g, HPLC purity are 99.2%, yield 76%；1H NMR(400M,CDCl3):
12.21 (s, 1H), 7.97-7.96 (m, 2H), 7.74 (s, 1H), 7.49-7.48 (m, 2H), 7.25 (d, J=12.0Hz, 2H),
6.83(dd,J1=8.0Hz, J2=4.0Hz, 1H), 3.12 (s, 1H), MS (ESI) m/z:368.3[M+H]+；Anal.Calcd
for C19H11Cl2N3O:C,61.98；H,3.01；N,11.41.Found:C,62.26；H,3.07；N,11.53.
Embodiment 17
Anti-tumor activity test
Growth period breast cancer cell MCF-7 is collected, the anticancer activity of compound is measured with MTS method, by cell with suitable
When (every milliliter 4 × 10 of concentration4A cell) it is added in 96 porocyte culture plates and (obtains culture solution containing 10% tire calf serum and be made into list
A cell suspension), after culture 24 hours, in 37 DEG C, the CO that volumetric concentration is 5%2Under the conditions of make with the compound of various concentration
With 72 hours, then the mixture of MTS (final mass concentration 2mg/mL) and DMS (30 μM of final molar concentration) are directly added into
In celliferous culture medium, continue to set incubator incubation 4h.After acting on 4h, liquid is discarded supernatant, 150 μ LDMSO, vibration is added in every hole
It swings, cell survival rate measures absorptivity of the metabolin of MTS effect under enzyme linked immunological monitor 490nm wavelength by it.
Preliminary biological activity test shows that such compound has inhibition to make in cancer cell in breast cancer cell MCF-7
With.
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (6)
1. a kind of new indole and pyridone drug molecule and its preparation method and application, it is characterised in that the trypoline ketone
The structure of drug molecule is：Wherein R is to fluorobenzene, quinoline and indoles.
2. a kind of new indole according to claim 1 and pyridone drug molecule and preparation method thereof, it is characterised in that
The specific steps are：
A, 3,5- dichloroaniline is added in the mixed solution of water and sulfuric acid, 0 DEG C is cooled to after mixing evenly, in stirring condition
Under, the aqueous solution dissolved with sodium nitrite is added dropwise, carries out diazo-reaction and obtains solution A；It is configured in another reaction flask
Dissolved with the aqueous solution of barium hydroxide, under the conditions of 0 DEG C, the ethyl alcohol dissolved with ethyl pyruvate is slowly added dropwise, is stirred after dripping
It uniformly prepares and obtains solution B；Solution A as under the conditions of 0 DEG C, solution B is added dropwise to solution A by slow obtain, and is heated up after dripping
The condensation reaction of amine aldehyde, filtering reacting liquid occurs to 40 DEG C of reaction a period of times, then extracts filtrate with ether, is used after merging organic phase
Anhydrous magnesium sulfate is dry, is recrystallized to give ethyl -2- (2- (3,5- dichlorophenyl) through n-hexane and acetone mixed solution after concentration
Hydrazono-) propionic acid；
B, ethyl -2- (2- (3,5- dichlorophenyl) hydrazono-) propionic acid and polyphosphoric acids are added in toluene, heat 45 DEG C, stirring
Open vacuum after reaction a period of time, divide exactly toluene, ice water is then added, filter reaction solution after mixing evenly, filter cake through just oneself
Alkane is recrystallized to give 4,6- dichloro-indole Ethyl formate；
C, 4,6- dichloro-indole Ethyl formate, sodium nitrite, potassium peroxydisulfate are added to formic acid, continue to stir under the conditions of 90 DEG C
Reaction is subsequently poured into water to raw material fully reacting, and it is multiple to be extracted with ethyl acetate reaction solution, is merged after organic phase with anhydrous sulphur
Sour sodium is dry, through isolated 2- nitro -4, the 6- dichloro-indole Ethyl formate of silica gel column chromatography after concentration of reaction solution；
D, 2- nitro -4,6- dichloro-indole Ethyl formate and catalyst palladium carbon are added in methanol, hydrogen are passed through in autoclave,
Pressure reaches certain pressure, and reaction temperature is 40 DEG C, reacts to raw material fully reacting, filtering reacting liquid, filtrate is concentrated to get pure
Net 2- amido -4,6- dichloro-indole Ethyl formate；
E, by 2- amido -4,6- dichloro-indole Ethyl formate adding into dichloromethane, triethylamine is added, is cooled to 10 DEG C,
4- chloroformyl ethyl acetate is slowly added dropwise, overnight, TLC monitors raw material fully reacting for room temperature reaction, adds methylene chloride dilution
Reaction solution, twice, anhydrous sodium sulfate is dry for washing, is spin-dried for both obtaining 2- formamido ethyl acetate -4,6- dichloro-indole formic acid second
Ester；
F, 2- formamido ethyl acetate -4,6- dichloro-indole Ethyl formate is added in tetrahydrofuran, then uncle is added portionwise
Butanol potassium, reaction temperature control are added ice water after less than 25 DEG C, reacting a period of time and are quenched, and are adjusted with the HCl of 2mol/L anti-
Answering liquid pH is 3, and filtering, vacuum drying obtains off-white powder product 7, bis- chloro-4-hydroxyl -2- carbonyl -2,5- dihydro -1H- of 9-
Pyrido [3,2-b] indole -3-carboxylic acid ethyl ester；
G, add 7,9- bis- chloro-4-hydroxyl -2- carbonyl -2,5- dihydro -1H- pyrido [3,2-b] indoles-in batches in hydrochloric acid solution
3- Ethyl formate is heated to 100 DEG C, and reaction overnight, is spin-dried for reaction dissolvent, then washed with ether, and vacuum drying obtains off-white color
Solid 7,9- bis- chloro-4-hydroxyl -2- carbonyl -2,5- dihydro -1H- pyrido [3,2-b] indoles；
H, it in closed reaction flask, is added portionwise into phosphorus oxychloride dissolved with 7,9-, bis- chloro-4-hydroxyl -2- carbonyl -2,5- bis-
The toluene solution of hydrogen -1H- pyrido [3,2-b] indoles is slowly heated to 100 DEG C, and overnight, TLC monitoring raw material has reacted for reaction
Quan Hou, vacuum is spin-dried for phosphorus oxychloride and solvent toluene obtains the ethyl acetate that 10 times of volumes are added in Red oil concentrate, washing
Three times, organic phase is separated, then washed with sodium chloride solution, dry, rotation reaction solution obtains chloro- carbonyl -2 2- the chloro- 4- of 7,9- bis-,
5- dihydro -1H- pyrido [3,2-b] indoles；
I, chloro- 2- carbonyl -2,5- dihydro -1H- pyrido [3, the 2-b] indoles of the chloro- 4- of 7,9- bis- is added in tetrahydrofuran, then
Potassium phosphate and boronic acid derivatives are added, is heated to 100 DEG C, is added to first after concentration is extracted with ethyl acetate after reaction a period of time
In pure and mild dilute hydrochloric acid and Isosorbide-5-Nitrae-dioxane mixed solution, room temperature reaction to raw material fully reacting, vacuum concentration, ether washing,
It obtains
3. a kind of new indole according to claim 2 and pyridone drug molecule, it is characterised in that：Described in step A
N-hexane and acetone volume ratio be 2:1.
4. a kind of new indole according to claim 2 and pyridone drug molecule, it is characterised in that：Described in step D
Certain pressure be 0.05~0.4MPa.
5. a kind of new indole according to claim 2 and pyridone drug molecule, it is characterised in that：Described in step I
Chloro- 2- carbonyl -2,5- dihydro -1H- pyrido [3,2-b] indoles of the chloro- 4- of 7,9- bis- and the inventory molar ratio of potassium phosphate be
1:2~4.
6. a kind of new indole as described in claim 1 and pyridone drug molecule application in preparation of anti-tumor drugs.
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| CN109160914A (en) * | 2018-11-17 | 2019-01-08 | 重庆文理学院 | A kind of synthetic method of double trypoline analog derivatives and the application in antitumor |
| CN116283906A (en) * | 2023-03-28 | 2023-06-23 | 中山大学 | Oxindole derivative containing 2-pyridone heterocycle and preparation method and application thereof |
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| CN104693186B (en) * | 2014-12-31 | 2017-12-22 | 青岛黄海制药有限责任公司 | C F keys generation C N are bonded to the method that class medicine is dissolved in west in a kind of indole derivatives |
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| CN116283906B (en) * | 2023-03-28 | 2024-04-26 | 中山大学 | Oxindole derivative containing 2-pyridone heterocycle and preparation method and application thereof |
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