CN106632329B - The indole derivatives and its synthetic method of a kind of pyridine piperidines indoles and ring structure - Google Patents
The indole derivatives and its synthetic method of a kind of pyridine piperidines indoles and ring structure Download PDFInfo
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract
The invention belongs to pharmaceutical technology fields, and in particular to the indole derivatives and its synthetic method of a kind of pyridine piperidines indoles and ring structure.Under inert gas shielding of the present invention, N pyridyl group indoles, tolans, Co catalysts, silver acetate AgOAc, a water acetic acid copper Cu (OAc) are sequentially added in reaction tube2·H2O, silver tetrafluoroborate AgBF4And organic solvent, 16 30h are stirred to react under the conditions of 130 140 DEG C, obtain pyrido [2', 1':2,3] then piperidines [1,6 a] indoles salt is added absolute methanol, sodium borohydride, is stirred to react 1.5 2.5h under the conditions of temperature≤5 DEG C, obtains target product.Target product of the present invention is a kind of important alkaloid, has high bioactivity even medical value, synthetic method step is simple, high income.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of pyridine piperidines indoles and the indole derivatives of ring structure and
Its synthetic method.
Background technology
The indole derivatives of pyridine piperidines indoles and ring structure have important biology living as a kind of important alkaloid
Property and certain medical value.Pyridine piperidines indoles and ring structure indole derivatives (the bis- hydrogen -4H- pyridos of 6,7- [2 ',
1’:2,3] piperidines simultaneously [1,6-a] indole derivatives) it is a kind of new alkaloid, in the prior art it is not yet reported that this biology
Alkali and its synthetic method.
Chinese patent CN102741251B discloses that a kind of pyridine cyclo-derivative, its pharmaceutically acceptable salt, it is vertical
Body isomers or its solvated compounds：Wherein R1, R2, R3, Q, X and Y are defined as in the description；The invention further relates to these changes
The preparation method for closing object is preparing treatment and/or is preventing non-containing the pharmaceutical composition of these compounds and these compounds
Insulin-dependent diabetes mellitus, hyperglycemia, hyperlipidemia, insulin resistance drug in application.But above-mentioned patent step is multiple
It is miscellaneous, low yield.
Invention content
To overcome drawbacks described above, the purpose of the present invention is to provide a kind of indoles of pyridine piperidines indoles and ring structure derivatives
Object and its synthetic method.
To achieve the above object, the present invention adopts the following technical scheme that：
The indole derivatives of a kind of pyridine piperidines indoles and ring structure, chemical structure of general formula are：
Wherein, the R1For a kind of in hydrogen, alkyl, halogen, alkoxy and ester group, R2To be a kind of in hydrogen, alkyl and halogen,
R3It is a kind of in hydrogen, alkyl, halogen and nitro.
A kind of synthetic method of the indole derivatives of above-mentioned pyridine piperidines indoles and ring structure, includes the following steps：
(1) under inert gas shielding, N- pyridyl group indoles, tolans, Co catalysts, vinegar are sequentially added in reaction tube
Sour silver AgOAc, a water acetic acid copper Cu (OAc)2·H2O, silver tetrafluoroborate AgBF4And organic solvent；
(2) 16-30h is stirred to react under the conditions of step (1) reaction tube being placed in 130-140 DEG C；
(3) after completion of the reaction, reaction tube is cooled to room temperature step (2), and reaction mixture desalination washs, and concentration is pure
Change, obtains pyrido [2', 1':2,3] piperidines [1,6-a] indoles salt；
(4) by pyrido [2', 1':2,3] piperidines [1,6-a] indoles salt is dissolved in absolute methanol, and boron hydrogen is then added
Change sodium, 1.5-2.5h is stirred to react under the conditions of temperature≤5 DEG C；
(5) after reaction, reaction tube is cooled to room temperature step (4), and reaction mixture plus water are extracted liquid, extraction, brine
Washing, dry, purifying obtains target product.
Preferably, step (1) the N- pyridyl groups indoles, tolans, Co catalysts, silver acetate, a water acetic acid copper, four
Silver fluoborate, sodium borohydride the amount ratio of substance be：1:1-1.2:0.018-0.022：0.036-0.043:0.9-1.1:0.9-
1.1：The amount ratio of 3.5-4.5, the N- pyridyl groups indoles and organic solvent is 1mmol：8-15mL.
Preferably, step (1) Co catalysts are CoCp (CO) I2。
Preferably, step (1) organic solvent is 1,2- dichloroethanes.
Preferably, step (3) washer solvent is methanol or dichloromethane.
Preferably, step (5) extraction is methanol or dichloromethane with solvent.
Preferably, step (3) purifying is silicagel column column chromatography, and column chromatography condition is：200-300 mesh silica gel, elution
Agent is dichloromethane and methanol mixed solution, and the two volume ratio is 20：1.
Preferably, step (5) purifying is silicagel column column chromatography, and column chromatography condition is：200-300 mesh silica gel, elution
Agent is n-hexane and ethyl acetate mixture, and the two volume ratio is 50：1.
The synthetic method of the indole derivatives of pyridine piperidines indoles of the present invention and ring structure, reaction formula are as follows：
Wherein, the R1For a kind of in hydrogen, alkyl, halogen, alkoxy and ester group, R2To be a kind of in hydrogen, alkyl and halogen,
R3It is a kind of in hydrogen, alkyl, halogen and nitro.
The positive beneficial effect of the present invention：
It is a kind of important 1. the indole derivatives of pyridine piperidines indoles of the present invention and ring structure are nitrogen-containing heterocycle compound
Alkaloid has high bioactivity and medical value, and the indole derivatives of pyridine piperidines indoles of the present invention and ring structure
Synthetic method step it is simple, 66% or more yield, high income.
Specific implementation mode
With reference to some specific implementation modes, the present invention is further described.
Embodiment 1
The indole derivatives of a kind of pyridine piperidines indoles and ring structure, chemical structure of general formula are：
The synthetic method of the indole derivatives of above-mentioned pyridine piperidines indoles and ring structure, includes the following steps：
(1) under nitrogen protection, N- pyridyl group indoles 0.20mmol, tolans are sequentially added in schlenk pipes
0.2mmol, Co catalysts CoCp (CO) I21.8mol%, silver acetate AgOAc 3.6mol%, a water acetic acid copper Cu
(OAc)2·H2O 0.22mmol, silver tetrafluoroborate AgBF40.22mmol and 1,2- dichloroethanes 3mL；
(2) step (1) reaction tube is placed under the conditions of 130 DEG C of oil baths and is stirred to react 30h；
(3) after completion of the reaction, reaction tube is cooled to room temperature, and reaction mixture desalination is washed with dichloromethane, concentration,
Column chromatography condition purifies, and column chromatography condition is：200-300 mesh silica gel, eluant, eluent are dichloromethane and methanol mixed solution, the two
Volume ratio is 20：1, obtain pyrido [2', 1':2,3] piperidines [1,6-a] indoles salt；
(4) by pyrido [2', 1':2,3] piperidines [1,6-a] indoles salt is dissolved in absolute methanol, and boron hydrogen is then added
Change sodium 0.9mmol, 1.5h is stirred to react under the conditions of 2 DEG C of temperature；
(5) after reaction, reaction tube is cooled to room temperature step (4), and reaction mixture plus water are extracted liquid, extracted with methanol
It takes, salt water washing, dry, silicagel column column chromatography purifying, column chromatography condition is：200-300 mesh silica gel, eluant, eluent be n-hexane and
Ethyl acetate mixture, the two volume ratio are 50：1, obtain target product colorless solid 55.2mg, yield 71%, mp.91-
93℃.1H NMR (400MHz, CDCl3) δ 7.26-6.79 (m, 13H), 5.85 (dd, J=16.7,13.9Hz, 3H), 5.58 (d,
J=9.7Hz, 1H), 3.68 (q, J=18.5Hz, 2H), 2.93-2.67 (m, 1H), 2.48-2.01 (m, 4H) .13C NMR
(101MHz,CDCl3)δ141.34,137.59,136.30,135.15,132.69,132.07,131.41,130.29,
130.11,129.04,128.71,127.88,127.72,127.49,127.45,125.82,125.73,122.25,119.67,
107.67,107.01,95.92,67.02,49.05,26.28,21.49.HRMS m/z(ESI)Calcd for C28H25N2[M
+H+],389.2012,found 389.2017。
Embodiment 2
The indole derivatives of a kind of pyridine piperidines indoles and ring structure, chemical structure of general formula are：
The synthetic method of the indole derivatives of above-mentioned pyridine piperidines indoles and ring structure, includes the following steps：
(1) under nitrogen protection, N- pyridyl group indoles 0.20mmol, tolans are sequentially added in schlenk pipes
0.22mmol, Co catalysts CoCp (CO) I22.0mol%, silver acetate AgOAc 4.0mol%, a water acetic acid copper Cu
(OAc)2·H2O 0.20mmol, silver tetrafluoroborate AgBF40.20mmol and 1,2- dichloroethanes 2mL；
(2) step (1) reaction tube is placed under the conditions of 135 DEG C of oil baths and is stirred to react for 24 hours；
(3) after completion of the reaction, reaction tube is cooled to room temperature, and reaction mixture desalination is washed with dichloromethane, concentration,
Column chromatography condition purifies, and column chromatography condition is：200-300 mesh silica gel, eluant, eluent are dichloromethane and methanol mixed solution, the two
Volume ratio is 20：1, obtain pyrido [2', 1':2,3] piperidines [1,6-a] indoles salt；
(4) by pyrido [2', 1':2,3] piperidines [1,6-a] indoles salt is dissolved in absolute methanol, and boron hydrogen is then added
Change sodium 0.8mmol, 2h is stirred to react under the conditions of 0 DEG C of temperature；
(5) after reaction, reaction tube is cooled to room temperature step (4), and reaction mixture plus water are extracted liquid, use dichloromethane
Extraction, salt water washing is dry, the purifying of silicagel column column chromatography, and column chromatography condition is：200-300 mesh silica gel, eluant, eluent are n-hexane
And ethyl acetate mixture, the two volume ratio are 50：1, obtain target product colorless solid 63.0mg, yield 77%,
mp.100-102℃.1H NMR(400MHz,CDCl3)δ7.37(s,1H),7.25(s,1H),7.23-6.90(m,11H),6.01-
5.82 (m, 3H), 5.68 (d, J=10.0Hz, 1H), 3.77 (q, J=18.7Hz, 2H), 3.31-2.72 (m, 1H), 2.32 (d, J
=16.7Hz, 1H)13C NMR(101MHz,CDCl3)δ142.23,137.43,137.16,134.78,132.63,131.33,
130.88,130.12,127.95,127.89,127.59,127.46,126.00,125.53,125.44,120.74,119.05,
108.70,106.42,95.66,66.99,49.05,26.28.HRMS m/z(ESI)Calcd for C27H22N2Cl[M+H+],
409.1472,found 409.1477。
Embodiment 3
The indole derivatives of a kind of pyridine piperidines indoles and ring structure, chemical structure of general formula are：
The synthetic method of the indole derivatives of above-mentioned pyridine piperidines indoles and ring structure, includes the following steps：
(1) under nitrogen protection, N- pyridyl group indoles 0.20mmol, tolans are sequentially added in schlenk pipes
0.22mmol, Co catalysts CoCp (CO) I22.0mol%, silver acetate AgOAc 4.0mol%, a water acetic acid copper Cu
(OAc)2·H2O 0.20mmol, silver tetrafluoroborate AgBF40.20mmol and 1,2- dichloroethanes 2mL；
(2) step (1) reaction tube is placed under the conditions of 135 DEG C of oil baths and is stirred to react for 24 hours；
(3) after completion of the reaction, reaction tube is cooled to room temperature, and reaction mixture desalination is washed with dichloromethane, concentration,
Column chromatography condition purifies, and column chromatography condition is：200-300 mesh silica gel, eluant, eluent are dichloromethane and methanol mixed solution, the two
Volume ratio is 20：1, obtain pyrido [2', 1':2,3] piperidines [1,6-a] indoles salt；
(4) by pyrido [2', 1':2,3] piperidines [1,6-a] indoles salt is dissolved in absolute methanol, and boron hydrogen is then added
Change sodium 0.8mmol, 2h is stirred to react under the conditions of 0 DEG C of temperature；
(5) after reaction, reaction tube is cooled to room temperature step (4), and reaction mixture plus water are extracted liquid, use dichloromethane
Extraction, salt water washing is dry, the purifying of silicagel column column chromatography, and column chromatography condition is：200-300 mesh silica gel, eluant, eluent are n-hexane
And ethyl acetate mixture, the two volume ratio are 50：1, obtain target product colorless solid, 69.6mg, yield 86%,
mp.99-101℃.1H(400MHz,CDCl3) δ 7.25 (s, 1H), 7.23-7.00 (m, 10H), 6.92 (s, 1H), 6.78 (d, J=
8.6Hz, 1H), 6.34-5.80 (m, 3H), 5.67 (d, J=9.7Hz, 1H), 4.08-3.50 (m, 5H), 2.90 (t, J=
16.3Hz, 1H), 2.33 (d, J=16.3Hz, 1H)13CNMR(101MHz,CDCl3)δ154.38,141.38,137.49,
136.91,135.06,131.38,130.31,130.25,129.57,127.88,127.74,127.49,127.42,125.83,
125.68,110.37,108.55,106.90,102.22,96.14,67.12,55.88,49.03,26.28.HRMS m/z
(ESI)Calcd for C28H25N2O[M+H+],405.1961,found 405.1966。
Embodiment 4
The indole derivatives of a kind of pyridine piperidines indoles and ring structure, chemical structure of general formula are：
The synthetic method of the indole derivatives of above-mentioned pyridine piperidines indoles and ring structure, includes the following steps：
(1) under nitrogen protection, N- pyridyl group indoles 0.20mmol, tolans are sequentially added in schlenk pipes
0.22mmol, Co catalysts CoCp (CO) I22.0mol%, silver acetate AgOAc 4.0mol%, a water acetic acid copper Cu
(OAc)2·H2O 0.20mmol, silver tetrafluoroborate AgBF40.20mmol and 1,2- dichloroethanes 2mL；
(2) step (1) reaction tube is placed under the conditions of 135 DEG C of oil baths and is stirred to react for 24 hours；
(3) after completion of the reaction, reaction tube is cooled to room temperature, and reaction mixture desalination is washed with dichloromethane, concentration,
Column chromatography condition purifies, and column chromatography condition is：200-300 mesh silica gel, eluant, eluent are dichloromethane and methanol mixed solution, the two
Volume ratio is 20：1, obtain pyrido [2', 1':2,3] piperidines [1,6-a] indoles salt；
(4) by pyrido [2', 1':2,3] piperidines [1,6-a] indoles salt is dissolved in absolute methanol, and boron hydrogen is then added
Change sodium 0.8mmol, 2h is stirred to react under the conditions of 0 DEG C of temperature；
(5) after reaction, reaction tube is cooled to room temperature step (4), and reaction mixture plus water are extracted liquid, use dichloromethane
Extraction, salt water washing is dry, the purifying of silicagel column column chromatography, and column chromatography condition is：200-300 mesh silica gel, eluant, eluent are n-hexane
And ethyl acetate mixture, the two volume ratio are 50：1, obtain target product colorless solid, 63.6mg, yield 81%,
mp.99-101℃.1H NMR(400MHz,CDCl3) δ 7.18-6.99 (m, 12H), 6.77 (td, J=9.1,2.0Hz, 1H),
5.88-5.78 (m, 2H), 5.60 (d, J=10.0Hz, 1H), 3.69 (q, J=18.7Hz, 2H), 2.90-2.77 (m, 1H),
2.25 (d, J=16.8Hz, 1H)13C NMR(101MHz,CDCl3) δ 158.19 (d, J=233.9Hz), 137.24,134.84,
131.36,130.15,127.95,127.91,127.87,127.57,127.46,125.97 125.59,108.55 (d, J=
26.3Hz), 108.20 (d, J=9.9Hz), 104.84,104.72 (d, J=23.7Hz), 67.08,48.96,26.18.HRMS
m/z(ESI)Calcd for C27H22FN2[M+H+],393.1762,found 393.1767。
Embodiment 5
The indole derivatives of a kind of pyridine piperidines indoles and ring structure, chemical structure of general formula are：
The synthetic method of the indole derivatives of above-mentioned pyridine piperidines indoles and ring structure, includes the following steps：
(1) under nitrogen protection, N- pyridyl group indoles 0.20mmol, tolans are sequentially added in schlenk pipes
0.24mmol, Co catalysts CoCp (CO) I22.2mol%, silver acetate AgOAc 4.3mol%, a water acetic acid copper Cu
(OAc)2·H2O 0.18mmol, silver tetrafluoroborate AgBF40.18mmol and 1,2- dichloroethanes 1.6mL；
(2) step (1) reaction tube is placed under the conditions of 140 DEG C of oil baths and is stirred to react 16h；
(3) after completion of the reaction, reaction tube is cooled to room temperature, and reaction mixture desalination is washed with methanol, concentration, column layer
Analysis condition purifies, and column chromatography condition is：200-300 mesh silica gel, eluant, eluent are dichloromethane and methanol mixed solution, the two volume
Than being 20：1, obtain pyrido [2', 1':2,3] piperidines [1,6-a] indoles salt；
(4) by pyrido [2', 1':2,3] piperidines [1,6-a] indoles salt is dissolved in absolute methanol, and boron hydrogen is then added
Change sodium 0.7mmol, 2.5h is stirred to react under the conditions of 5 DEG C of temperature；
(5) after reaction, reaction tube is cooled to room temperature step (4), and reaction mixture plus water are extracted liquid, extracted with methanol
It takes, salt water washing, dry, silicagel column column chromatography purifying, column chromatography condition is：200-300 mesh silica gel, eluant, eluent be n-hexane and
Ethyl acetate mixture, the two volume ratio are 50：1, obtain target product colorless solid, 53.1mg, 66%, mp.99-101
℃.1H NMR(400MHz,CDCl3) δ 7.34 (t, J=7.8Hz, 1H), 7.15 (d, J=6.0Hz, 1H), 7.02 (dd, J=
16.1,7.7Hz, 2H), 6.98-6.89 (m, 6H), 6.85 (d, J=7.6Hz, 2H), 6.03-5.73 (m, 2H), 5.59 (d, J=
9.9Hz, 1H), 3.67 (q, J=18.8Hz, 2H), 2.99-2.68 (m, 1H), 2.33-2.30 (m, 1H), 2.19 (s, 6H)13C
NMR(101MHz,CDCl3)δ141.20,137.41,135.00,134.63,134.11,132.05,131.17,129.90,
129.60,128.62,128.50,128.17,127.44,125.64,120.54,119.76,119.63,108.03,106.63,
95.86,66.86,49.05,26.29,21.27,21.15.HRMS m/z(ESI)Calcd for C29H27N2[M+H+],
403.2169,found 403.2166。
Biological activity test
1. experiment material：DPPH free radicals, vitamin C, ultraviolet specrophotometer.
2. experimental procedure：A. distinguish the pyridine piperidines indoles and ring structure of precise 2.0mg embodiment of the present invention 1-5
Indole derivatives are settled to l0mL with anhydrous ethanol solvent, are configured to the sample prepare liquid of a concentration of 0.20mg/mL respectively, will
It is spare that above-mentioned prepare liquid by 2 times, 4 times, 8 times, 16 times, 32 times, 64 times, 128 times is diluted to series concentration；Precise again
2.0mg vitamin Cs, are equally settled to l0mL with anhydrous ethanol solvent, and the positive control sample for being configured to 0.20mg/mL is to be measured
Liquid；If absolute ethyl alcohol is blank control.
B. precise 8.5mg DPPH are configured to a concentration of 0.085mg/mL solution for standby with dichloromethane, meanwhile, it is accurate
Each prepare liquid 2mL is really weighed, the DPPH solution (0.085mg/mL) of 2mL is separately added into, 30min is stood after shaking up, at 517nm
Absorbance is measured, calculates clearance rate of each compound to DPPH free radicals, experimental result is shown in Table 1.
DPPH free radical scavenging activity calculation formula：Clearance rate (%)=[1- (A1-A2)/A3] × 100%,
Wherein, A1-2mL samples prepare liquid+2mLDPPH solution, A2-2mL sample prepare liquid+2mL absolute ethyl alcohols, A3-2mL
DPPH solution+2mL absolute ethyl alcohols.
Clearance rate (n=6) of the indole derivatives of 1 embodiment 1-5 of table to DPPH free radicals
Note：* P ＜ 0.01 are represented.
As shown in Table 1, the indole derivatives of the pyridine piperidines indoles of 1-5 of the embodiment of the present invention and ring structure are to DPPH freedom
Base has apparent scavenging effect, hence it is evident that it is better than positive control drug vitamin C, therefore, the pyridine piperidines of 1-5 of the embodiment of the present invention
The very strong bioactivity of indole derivatives of indoles and ring structure.
Claims (9)
1. the indole derivatives of a kind of pyridine piperidines indoles and ring structure, which is characterized in that its chemical structure of general formula is：
Wherein, the R1For a kind of in hydrogen, alkyl, halogen, alkoxy and ester group, R2For a kind of in hydrogen, alkyl and halogen, R3For
It is a kind of in hydrogen, alkyl, halogen and nitro.
2. a kind of synthetic method of the indole derivatives of pyridine piperidines indoles described in claim 1 and ring structure, feature exist
In including the following steps：
(1) under inert gas shielding, N- pyridyl group indoles, tolans, Co catalysts, silver acetate are sequentially added in reaction tube
AgOAc, a water acetic acid copper Cu (OAc)2·H2O, silver tetrafluoroborate AgBF4And organic solvent；
(2) 16-30h is stirred to react under the conditions of step (1) reaction tube being placed in 130-140 DEG C；
(3) after completion of the reaction, reaction tube is cooled to room temperature step (2), and reaction mixture desalination washs, concentrates, and purifying obtains
To pyrido [2', 1':2,3] piperidines [1,6-a] indoles salt；
(4) by pyrido [2', 1':2,3] piperidines [1,6-a] indoles salt is dissolved in absolute methanol, and sodium borohydride is then added,
1.5-2.5h is stirred to react under the conditions of temperature≤5 DEG C；
(5) after reaction, reaction tube is cooled to room temperature step (4), and reaction mixture plus water are extracted liquid, extracted, salt water washing,
Dry, purifying obtains target product.
3. the synthetic method of the azole derivatives of pyridine piperidines indoles according to claim 2 and ring structure, feature exist
In step (1) the N- pyridyl groups indoles, tolans, Co catalysts, silver acetate, a water acetic acid copper, silver tetrafluoroborate, boron
The amount ratio of the substance of sodium hydride is：1:1-1.2:0.018-0.022：0.036-0.043:0.9-1.1:0.9-1.1：3.5-4.5
The amount ratio of the N- pyridyl groups indoles and organic solvent is 1mmol：8-15mL.
4. the synthetic method of the azole derivatives of pyridine piperidines indoles according to claim 2 and ring structure, feature exist
In step (1) Co catalysts are CoCp (CO) I2。
5. the synthetic method of the azole derivatives of pyridine piperidines indoles according to claim 2 and ring structure, feature exist
In step (1) organic solvent is 1,2- dichloroethanes.
6. the synthetic method of the azole derivatives of pyridine piperidines indoles according to claim 2 and ring structure, feature exist
In step (3) washer solvent is methanol or dichloromethane.
7. the synthetic method of the azole derivatives of pyridine piperidines indoles according to claim 2 and ring structure, feature exist
In step (5) extraction is dichloromethane with solvent.
8. the synthetic method of the azole derivatives of pyridine piperidines indoles according to claim 2 and ring structure, feature exist
In step (3) purifying is silicagel column column chromatography, and column chromatography condition is：200-300 mesh silica gel, eluant, eluent are dichloromethane
With methanol mixed solution, the two volume ratio is 20：1.
9. the synthetic method of the azole derivatives of pyridine piperidines indoles according to claim 2 and ring structure, feature exist
In step (5) purifying is silicagel column column chromatography, and column chromatography condition is：200-300 mesh silica gel, eluant, eluent be n-hexane and
Ethyl acetate mixture, the two volume ratio are 50：1.
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