CN102002040A - Synthesis method of triazol pyridine ring compound - Google Patents
Synthesis method of triazol pyridine ring compound Download PDFInfo
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- CN102002040A CN102002040A CN2009100578595A CN200910057859A CN102002040A CN 102002040 A CN102002040 A CN 102002040A CN 2009100578595 A CN2009100578595 A CN 2009100578595A CN 200910057859 A CN200910057859 A CN 200910057859A CN 102002040 A CN102002040 A CN 102002040A
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Abstract
The invention relates to a synthesis method of a triazol pyridine ring compound, which mainly solves the technical problems of low yield, high synthesizing cost, poor applicability and the like existing in the traditional synthesis method. The synthesis method comprises the following steps of: (1) making substituted 2-hydrazine-based pyridine react with substituted benzaldehyde, and (2) filtering sediments generated by reaction, dissolving the sediments in a solvent and adding lead tetraacetate, and refluxing to obtain a target product. The target product can be also obtained with a one-pot method by directly carry out the step (2) without separating the sediments. The synthesis method has the advantages of easy obtainment of simple raw materials, simple synthesizing steps, mild reaction condition and higher yield.
Description
Technical field:
The present invention relates to the synthetic method of the important potential drug molecule of class Triazolopyridine cyclic cpds.
Background technology:
Triazole compounds is the important drug molecule of a class, can be used for agricultural chemicals and make sterilant, plant-growth regulator.For example commercial paclobutrazol, triapenthenol etc. have very strong growth regulating effect to farm crop.Pharmaceutically have functions such as antibiotic, anti-inflammatory, spasmolytic, anti-platelet aggregation.The Triazolopyridine cyclic cpds has report as the important drug molecule of a class decades ago.
These reports mainly comprise two class synthetic methods:
1) reaction of the aroyl chloride of 2-hydrazino pyridine of Qu Daiing and replacement generates hydrazides, and refluxing in phosphorus oxychloride then generates the Triazolopyridine cyclic cpds.[J.D.Bower?and?F.P.Doyle，Journal?of?the?Chemical?Society，1957，727-732]
This method is used the highly toxic product phosphorus oxychloride in second step, operation danger, and yield is lower.
Its reaction formula is as follows:
2) reaction of 2-hydrazino pyridine and aromatic aldehyde generates the pyridine hydrazone, adds the diacetoxy iodobenzene then, and heating generates the Triazolopyridine cyclic cpds in solvent.[Sadana，Anil?K.；Mirza，Yasmin；Aneja，Kamal?R.；Prakash，Om；EuropeanJournal?of?Medicinal?Chemistry，2003，38，5，533-536]
Additive diacetoxy iodobenzene less stable in this method, price is higher, is unfavorable for the industry amplification.
Its reaction formula is as follows:
Summary of the invention:
The object of the present invention is to provide a kind of synthetic method of important drugs molecule Triazolopyridine cyclic cpds, mainly solve the low or difficult storage of starting material of existing synthetic method yield, use problems such as hypertoxic raw material and cost are too high.Technical scheme of the present invention: the synthetic method of Triazolopyridine cyclic cpds may further comprise the steps:
The first step: the 2-hydrazino pyridine 1 with replacement is a raw material, and with phenyl aldehyde 2 back flow reaction in organic solvent that replaces, the reaction solution cold filtration obtains white solid precipitation pyridine hydrazone class Schiff's base 3.
Second step: the pyridine hydrazone class Schiff's base 3 that filtration is obtained is dissolved in the organic solvent and adds lead tetra-acetate 4, and back flow reaction is after aftertreatment can obtain Triazolopyridine cyclic cpds 5.
This reaction also can obtain by one kettle way, i.e. the first step reaction is not come out precipitate and separate, directly carries out the operation of second step.Chemical equation is as follows:
R wherein
1Be selected from a kind of in trifluoromethyl, bromo or the nitro, R
2Be selected from hydrogen base, methyl, chloro or fluorine-based etc. in a kind of.
Above-mentioned synthetic method, organic solvent are selected from tetrahydrofuran (THF), N, a kind of in dinethylformamide, toluene or the ethanol, and the first step reflux time is 1-3 hour, the second step reflux time is 16-24 hour.
The invention has the beneficial effects as follows: the invention provides a kind of synthetic route of Triazolopyridine cyclic cpds, can prepare this class important drugs molecule quickly and easily from raw material cheap, that be easy to get.In the raw material, aromatic aldehyde is chemical goods, and the 2-hydrazino pyridine of replacement can be filtered by the 2-chloropyridine hydrazinolysis that replaces and obtain, reported in the past that the document of this compounds compared, the preparation that the present invention is not only successful target compound, and aftertreatment is also safer, easy to operate.
Embodiment: following example helps to understand content of the present invention, the present invention includes but is not limited to following related content:
Embodiment 1
Method one:
The synthesis technique of tolyl between 6-(trifluoromethyl)-3--[1,2,4] triazole [4,3-a] and pyridine:
In single neck bottle of 25 milliliters, add 5 milliliters of dehydrated alcohols, tolyl aldehyde (2,1.2 mmole), 0.177 gram 2-diazanyl-5-5-flumethiazine (1 between 0.144 gram, 1.0 mmole) heating reflux reaction is 2 hours, the TLC monitoring, aromatic aldehyde is cooled to room temperature after disappearing substantially.Filter out the white solid pyridine hydrazone Schiff's base that generates in the reaction.It is dissolved in 8 milliliters of dry toluenes, adds 1.2 mmole lead tetra-acetate, 80 ℃ of heated and stirred 18 hours.Be cooled to room temperature, add 5 ml waters, filter out the solid of separating out, and use acetic acid ethyl dissolution.The organic layer saturated sodium bicarbonate, the salt water washing, and use anhydrous sodium sulfate drying.Remove by filter sodium sulfate, revolve and desolvate, resistates separates (petrol ether/ethyl acetate=1: 1) with the preparation thin-layer chromatography and obtains tolyl between 6-(trifluoromethyl)-3--[1,2,4] triazole [4,3-a] and pyridine.
Method two:
The synthesis technique of tolyl between 6-(trifluoromethyl)-3--[1,2,4] triazole [4,3-a] and pyridine:
In single neck bottle of 25 milliliters, add 5 milliliters of dehydrated alcohols, tolyl aldehyde (2,1.2 mmole), 0.177 gram 2-diazanyl-5-5-flumethiazine (1,1.0 mmole) reflux between 0.144 gram, the TLC monitoring, aromatic aldehyde is cooled to room temperature after disappearing substantially.Add 1.2 mmole lead tetra-acetate, 80 ℃ of heated and stirred 18 hours.Be cooled to room temperature, add 5 ml waters, filter out the solid of separating out, and use acetic acid ethyl dissolution.The organic layer saturated sodium bicarbonate, the salt water washing, and use anhydrous sodium sulfate drying.Remove by filter sodium sulfate, revolve and desolvate, resistates separates (petrol ether/ethyl acetate=1: 1) with the preparation thin-layer chromatography and obtains tolyl between 6-(trifluoromethyl)-3--[1,2,4] triazole [4,3-a] and pyridine.Productive rate: 57%.
Fusing point is: 94 ℃.Proton nmr spectra
1HNMR (CDCl
3, 300MHz): δ 8.60 (d, J=1.2Hz, 1H), 7.96 (d, J=9.6Hz, 1H), 7.66-7.39 (m, 5H); Mass spectrum (ESI source): C
14H
10F
3N
3M/z 278 (M
++ 1).
According to method one or the method two of embodiment 1, we have also synthesized following Triazolopyridine compounds:
Embodiment 2
With p-tolyl aldehyde replace among the embodiment 1 between tolyl aldehyde obtain 6-(trifluoromethyl)-3-p-methylphenyl-[1,2,4] triazole [4,3-a] and pyridine, organic solvent is a tetrahydrofuran (THF), and the first step reflux time is 1 hour, and the second step reflux time is 16 hours.
Productive rate: 78%.Its fusing point: 108 ℃.Proton nmr spectra
1HNMR (CDCl
3, 300MHz):: δ 8.58 (d, J=1.2Hz, 1H), 7.95 (d, J=9.6Hz, 1H), 7.72 (dd, J=1.8Hz, 6.6Hz, 2H), 7.46-7.38 (m, 3H); Mass spectrum (ESI source): C
14H
10F
3N
3M/z 278 (M
++ 1).
Embodiment 3
With o-methyl-benzene formaldehyde replace among the embodiment 1 between tolyl aldehyde obtain 6-(trifluoromethyl)-3-o-tolyl-[1,2,4] triazole [4,3-a] and pyridine, organic solvent is an ethanol, and the first step reflux time is 1.5 hours, and the second step reflux time is 20 hours.
Productive rate: 77%.Its fusing point: 83 ℃.Proton nmr spectra
1HNMR (CDCl
3, 300MHz):: δ 8.16 (d, J=1.2Hz, 1H), 7.98 (d, J=9.6Hz, 1H), 7.56-7.40 (m, 5H); Mass spectrum (ESI source): C
14H
10F
3N
3M/z 278 (M
++ 1).
Embodiment 4
With phenyl aldehyde replace among the embodiment 1 between tolyl aldehyde obtain 6-(trifluoromethyl)-3-phenyl-[1,2,4] triazole [4,3-a] and pyridine, organic solvent is N, dinethylformamide, the first step reflux time is 3 hours, and the second step reflux time is 22 hours.
Productive rate: 88%.Proton nmr spectra
1HNMR (CDCl
3, 300MHz):: δ 8.62 (s, 1H), 7.98 (d, J=9.6Hz, 1H), 7.83-7.61 (m, 5H), 7.45 (d, J=9.6Hz, 1H); Mass spectrum (ESI source): C
13H
8F
3N
3M/z 264.0[M
++ 1]
Embodiment 5
With 4-chloro-benzaldehyde replace among the embodiment 1 between tolyl aldehyde obtain 6-(trifluoromethyl)-3-rubigan-[1,2,4] triazole [4,3-a] and pyridine.
Productive rate: 86%.Its fusing point: 120 ℃; Proton nmr spectra
1HNMR (CDCl
3, 300MHz):: δ 8.56 (d, J=1.2Hz, 1H), 7.98 (d, J=9.6Hz, 1H), 7.80-7.62 (m, 4H), 7.45 (dd, J=1.5Hz, 9.6Hz, 1H); Mass spectrum (ESI source): C
13H
7ClF
3N
3M/z 298[M
++ 1].
Embodiment 6
With p-Fluorobenzenecarboxaldehyde replace among the embodiment 1 between tolyl aldehyde obtain 6-(trifluoromethyl)-3-to fluorophenyl-[1,2,4] triazole [4,3-a] and pyridine.
Productive rate: 81%.Its fusing point: 117 ℃.Proton nmr spectra
1HNMR (CDCl
3, 300MHz):: δ 8.54 (d, J=1.2Hz, 1H), 7.98 (d, J=9.6Hz, 1H), 7.85-7.80 (m, 2H), 7.45 (dd, J=1.5Hz, 9.6Hz, 1H), 7.38-7.32 (m, 2H); Mass spectrum (ESI source): C
13H
7F
4N
3M/z 282.0[M
++ 1].
Embodiment 7
With adjacent fluorobenzaldehyde replace among the embodiment 1 between tolyl aldehyde, replace the 2-diazanyl-5-5-flumethiazine among the embodiment 1 to obtain 6-bromo-3-neighbour fluorophenyl-[1,2,4] triazole [4,3-a] and pyridine with 2-diazanyl-5-bromopyridine.
Productive rate: 95%.Proton nmr spectra
1HNMR (CDCl
3, 400MHz):: δ 8.03 (t, J=1.2Hz, 1H), 7.79-7.69 (m, 2H), 7.57-7.52 (m, 1H), 7.36-7.24 (m, 3H); Mass spectrum (ESI source): C
12H
7BrFN
3M/z 291[M
++ 1].
Embodiment 8
With adjacent fluorobenzaldehyde replace among the embodiment 1 between tolyl aldehyde, replace the 2-diazanyl-5-5-flumethiazine among the embodiment 1 to obtain 8-bromo-3-neighbour fluorophenyl-[1,2,4] triazole [4,3-a] and pyridine with 2-diazanyl-3-bromopyridine.
Productive rate: 100%.Proton nmr spectra
1HNMR (CDCl
3, 400MHz): δ 7.88-7.76 (m, 2H), 7.56-7.50 (m, 2H), 7.34-7.19 (m, 2H), 6.74 (t, J=6.8Hz, 1H); Mass spectrum (ESI source): C
12H
7BrFN
3M/z 291[M
++ 1].
Embodiment 9
With adjacent fluorobenzaldehyde replace among the embodiment 1 between tolyl aldehyde, replace the 2-diazanyl-5-5-flumethiazine among the embodiment 1 to obtain 7-nitro-3-neighbour fluorophenyl-[1,2,4] triazole [4,3-a] and pyridine with 2-diazanyl-4-nitropyridine.
Productive rate: 89%.Proton nmr spectra
1HNMR (CDCl
3, 400MHz): δ 8.76 (d, J=1.6Hz, 1H), 8.04-8.01 (dd, J=3.6,7.6Hz, 1H), 7.86-7.82 (m, 1H), 7.65-7.57 (m, 2H), 7.40-7.32 (m, 2H); Mass spectrum (ESI source): C
12H
7FN
4O
2M/z 259[M
++ 1].
Claims (5)
1. the synthetic method of a Triazolopyridine cyclic cpds is characterized in that may further comprise the steps:
The first step: the 2-hydrazino pyridine 1 with replacement is a raw material, and with phenyl aldehyde 2 back flow reaction in organic solvent that replaces, the reaction solution cold filtration obtains white solid precipitation pyridine hydrazone class Schiff's base 3.
Second step: the pyridine hydrazone class Schiff's base 3 that filtration is obtained is dissolved in the organic solvent and adds lead tetra-acetate 4, and back flow reaction is after aftertreatment can obtain Triazolopyridine cyclic cpds 5;
Reaction formula is as follows:
R wherein
1Be selected from a kind of in trifluoromethyl, bromo or the nitro, R
2Be selected from hydrogen base, methyl, chloro or fluorine-based in a kind of.
2. the synthetic method of a kind of Triazolopyridine cyclic cpds according to claim 1 is characterized in that adopting the one kettle way reaction, i.e. the first step reaction is not come out precipitate and separate, directly carries out the reaction of second step.
3. the synthetic method of a kind of Triazolopyridine cyclic cpds according to claim 1 and 2 is characterized in that, described organic solvent is selected from tetrahydrofuran (THF), N, a kind of in dinethylformamide, toluene or the ethanol.
4. the synthetic method of a kind of Triazolopyridine cyclic cpds according to claim 1 and 2 is characterized in that the first step reflux time is 1-3 hour.
5. the synthetic method of a kind of Triazolopyridine cyclic cpds according to claim 1 and 2 is characterized in that, the second step reflux time is 16～24 hours.
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| US11369606B2 (en) | 2014-01-21 | 2022-06-28 | Janssen Pharmaceutica Nv | Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use |
| US12048696B2 (en) | 2014-01-21 | 2024-07-30 | Janssen Pharmaceutica Nv | Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use |
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