CN107325110B - Four circle heterocyclic ring benzothiophenes of one kind and quinoline compound and its synthetic method - Google Patents
Four circle heterocyclic ring benzothiophenes of one kind and quinoline compound and its synthetic method Download PDFInfo
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- CN107325110B CN107325110B CN201710601929.3A CN201710601929A CN107325110B CN 107325110 B CN107325110 B CN 107325110B CN 201710601929 A CN201710601929 A CN 201710601929A CN 107325110 B CN107325110 B CN 107325110B
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- quinoline
- benzothiophene
- circle heterocyclic
- synthetic method
- thioquinoline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
The invention discloses a kind of four circle heterocyclic ring benzothiophenes and quinoline compound and its synthetic methods.For the present invention using 3- thioquinoline -2- ketone as raw material, phosphorus oxychloride is solvent and dehydrating agent, and benzothiophene and quinoline are converted at 90-110 DEG C.Inventive substrate is cheap and easy to get with dehydrating agent, and reaction efficiency is high；It being compared with the traditional method, one-step synthesis method target product, synthesis step is few, and it is easy to operate, it is suitble to industrialized production.
Description
Technical field
The present invention relates to a kind of four circle heterocyclic ring benzothiophenes and quinoline compound and its synthetic methods, belong to fine chemistry industry production
The preparation field of product.
Background technique
Quaternary fused ring benzothiophene and quinoline are widely present in organic functional material and a variety of have valuable pharmacological active
Heterocyclic compound in, antimycotic (Bioorg.Med.Chem.2011,19,458), anticancer can be played
The physiology such as (J.Med.Chem.1997,40,2040) and viral infection resisting (Bioorg.Med.Chem.2007,15,686) are living
Property.Therefore, how efficiently there is such parallel heterocyclic compound important research to anticipate rapidly, using relatively simple Material synthesis
Justice.However, at present, synthesize that such compound is most traditional and common method, usually first synthesizes its precursor compound
Benzothiophene and quinolinone (EP0264124B1), using chloride dehydrate, hydro-reduction and etc. obtain corresponding target ring
System, and precursor compound structure is also complex, it usually needs it synthesizes to obtain from ortho-aminobenzoic acid by multistep.Together
When, to targetedly introduce substituent group in different ring systems, then it but will increase cost and synthesis difficulty.
Therefore, the new method for finding simple one kind, building benzothiophene efficiently, cheap and quinoline compound just seems outstanding
Its is important.
Summary of the invention
The present invention is intended to provide a kind of four circle heterocyclic ring benzothiophenes and quinoline compound and its synthetic method, realize and conform to the principle of simplicity
The method that single substrate efficiently constructs benzothiophene and quinoline a pair of horses going side by side Fourth Ring.
3- thioquinoline -2- ketone compound is the higher unique compounds of molecule intramolecular cyclization activity, it is existing at present compared with
For the mature easy method report for synthesizing the compound, finds after study, by selecting suitable dehydrating agent, this can be made
Class compound, which is efficiently cyclized, forms benzothiophene and chinoline backbone.In consideration of it, the present invention is that dehydrating agent can incite somebody to action using phosphorus oxychloride
3- thio quinoline-2-one Efficient Conversion is benzothiophene and quinoline.
The present invention provides a kind of four circle heterocyclic ring benzothiophenes and quinoline compound, structural formulas are as follows:
In structure above, Ar represents phenyl ring or the aromatic ring with different substituents, R1Represent H or aryl；R2It represents
With different electrical substituent groups.
The present invention provides a kind of four circle heterocyclic ring benzothiophenes and quinoline compounds, using 3- thioquinoline -2- ketone as raw material,
Phosphorus oxychloride is solvent and dehydrating agent, under the conditions of 90-110 DEG C can Efficient Conversion at benzothiophene and quinoline.
Reaction equation is as follows:
In the above reaction equation, Ar represents phenyl ring or the aromatic ring with different substituents, R1Represent hydrogen atom or aryl；
R2Representing has different electrical substituent groups.
Preferably, Ar=5-OMePh, R1=H, R2=H；
Ar=6-ClPh, R1=H, R2=H；
Ar=Ph, R1=Ph, R2=H；
Ar=Ph, R1=Ph, R2=Me.
The present invention about the definition of substituent group and phenyl ring be it is well known to those of ordinary skill in the art, herein and hereafter not
It is described in detail again.
Above-mentioned synthetic method specifically includes the following steps:
(1) 3- thioquinoline -2- ketone is put into dry reaction flask, phosphorus oxychloride reagent, stirring is added under room temperature
It makes it dissolve；
(2) it flows back 1-4 hours at a temperature of dissolved solution being heated to 90-110 DEG C；
(3) it after raw material fully reacting, is poured into cold water after reaction solution is cooled to room temperature, then adjusts PH with ammonium hydroxide and arrive
10, it is extracted with ethyl acetate 2-3 times, extract liquor is dry with anhydrous sodium sulfate；
(4) target product is recrystallized to obtain with n-hexane after extract liquor being concentrated.
In above-mentioned preparation method, the mol ratio of substrate 3- thioquinoline -2- ketone and phosphorus oxychloride is (0.1-1): 1, most
Excellent mol ratio is 0.5:1.
The optimal conditions of above-mentioned preparation method is 100 DEG C of reaction temperature, and the reaction time is 2 hours.
Reaction process of the invention relates generally to the dehydration of phosphorus oxychloride: first in phosphorus oxychloride and amide structure
Oxygen atom combines, and proton is removed in the form of HCl in the process；Further, with PO after oxygen atom is in conjunction with phosphorus atoms2Cl2
Form leave away, form isonitrile intermediate since neighbouring diphenyl sulfide electrophilicity is stronger can form new C- by nucleophilic attack
C key, and further by going aromatization to form final benzothiophene and quinoline.
Beneficial effects of the present invention:
(1) synthetic method of benzothiophene provided by the invention and quinoline has the advantage that substrate is cheap with dehydrating agent
It is easy to get, reaction efficiency is high；
(2) it is compared with the traditional method and (is shown below), one-step synthesis target product of the present invention, synthesis step is few, operation
Simply, it is suitble to industrialized production.
Specific embodiment
In conjunction with following specific embodiments, the present invention is described in further detail, but of the invention protects content not office
It is limited to following embodiment.Confirmation is compared with standard spectrogram by nucleus magnetic hydrogen spectrum for product structure.
Embodiment 1:
- 2 (1H) -one (1mmol, 283mg) of 3- thiophenyl -6- chloroquinoline is put into dry reaction flask, then room temperature
Lower addition 2mL phosphorus oxychloride reagent, back flow reaction under conditions of reaction flask is put into 100 DEG C, with TLC plate detect response situation, 2
Raw material fully reacting after hour.It is poured into after reaction solution is cooled to room temperature in 20mL cold water, uses second after adjusting PH to 10 with ammonium hydroxide
Acetoacetic ester extraction (each 20mL is extracted 3 times), anhydrous sodium sulfate is dry.It is recrystallized after extract liquor is concentrated with n-hexane, finally
Obtain pale yellow crystals, yield 77%.
M.p.190–191℃；1H NMR(CDCl3, 400MHz): δ 8.94 (s, 1H), 8.59 (d, 1H, J=7.5Hz),
7.81 (dd, 2H, J=8.10,9.0Hz), 7.59-7.44 (m, 3H), 6.80 (d, 1H, J=7.5), 3.96 (s, 3H).
Embodiment 2:
- 2 (1H) -one (1mmol, 288mg) of 3- thiophenyl -6- chloroquinoline is put into dry reaction flask, then room temperature
Lower addition 1mL phosphorus oxychloride reagent, back flow reaction under conditions of reaction flask is put into 110 DEG C, with TLC plate detect response situation, 4
Raw material fully reacting after hour.It is poured into after reaction solution is cooled to room temperature in 20mL cold water, adjusts PH to 10 with ammonium hydroxide, then use
Ethyl acetate extraction (each 20mL is extracted 3 times), it is dry with anhydrous sodium sulfate, it is recrystallized after extract liquor is concentrated with n-hexane,
Finally obtain colourless crystallization, yield 72%.
M.p.173–175℃；1HNMR(CDCl3, 400MHz): δ 8.63 (s, 1H), 8.57 (d, 1H, J=7.2Hz), 8.29
(s, 1H), 7.84 (d, 1H, J=8.1Hz), 7.66-7.52 (m, 3H).
Embodiment 3:
- 2 (1H) -one (1mmol, 329mg) of 3- thiophenyl -4- phenylchinoline is put into dry reaction flask, then often
Temperature is lower to be added 10mL phosphorus oxychloride reagent, and back flow reaction under conditions of reaction flask is put into 95 DEG C detects reaction feelings with TLC plate
Condition, raw material fully reacting after 2 hours.It is poured into after reaction solution is cooled to room temperature in 20mL cold water, adjusts PH to 10 with ammonium hydroxide, so
After (each 20mL, extract 3 times) is extracted with ethyl acetate, anhydrous sodium sulfate is dry.It is tied again after extract liquor is concentrated with n-hexane
Crystalline substance finally obtains pale yellow crystals, yield 80%.
M.p.168-170℃；1H NMR(CDCl3, 400MHz): δ 8.70 (d, 1H, J=7.2Hz), 8.36 (d, 1H, J=
8.4Hz), 7.86 (d, 1H, J=8.4Hz), 7.77 (t, 1H, J=8.4Hz), 7.67-7.57 (m, 7H), 7.52 (t, 1H, J=
7.2Hz)。
Embodiment 4:
- 2 (1H) -one (1mmol, 343mg) of 3- (to Tolylsulfanvl) -4- phenylchinoline is put into dry reaction flask,
Then 5mL phosphorus oxychloride reagent is added under room temperature, back flow reaction under conditions of reaction flask is put into 90 DEG C is detected anti-with TLC plate
Situation is answered, raw material fully reacting after 1 hour.It pours into after reaction solution is cooled to room temperature in 20mL cold water, is then adjusted with ammonium hydroxide
PH to 10 is extracted with ethyl acetate (each 20mL is extracted 3 times), then dry with anhydrous sodium sulfate, uses after extract liquor is concentrated
N-hexane recrystallization, finally obtains yellow needle-like crystals, yield 84%.
M.p.142-144℃；1H NMR(CDCl3, 400MHz): δ 8.51 (s, 1H), 8.35 (d, 1H, J=8.4Hz),
7.84 (d, 1H, J=8.4Hz), 7.75 (t, 1H, J=8.4Hz), 7.67-7.54 (m, 6H), 7.50 (t, 1H, 8.4Hz), 7.41
(d, 1H, J=8.0Hz), 2.59 (s, 3H).
Claims (5)
1. the synthetic method of a kind of four circle heterocyclic ring benzothiophenes and quinoline compound, the four circle heterocyclic rings benzothiophene and quinoline chemical combination
Object, using 3- thioquinoline -2- ketone as raw material, phosphorus oxychloride is solvent and dehydrating agent, is converted to benzo thiophene under the conditions of 90-110 DEG C
Pheno and quinoline；The structural formula of the benzothiophene and quinoline are as follows:
In structure above, Ar represents phenyl ring or the aromatic ring with different substituents, R1Represent H or aryl；R2Representative has
Different electrical substituent groups；
It is characterized by: the structural formula of the 3- thioquinoline -2- ketone are as follows:
In structure above, Ar represents phenyl ring or the aromatic ring with different substituents, R1Represent H or aryl；R2Representative has
Different electrical substituent groups.
2. the synthetic method of four circle heterocyclic rings benzothiophene according to claim 1 and quinoline compound, it is characterised in that:
In the structural formula, Ar=5-OMePh, R1=H, R2= H；
Or Ar=6-ClPh, R1=H, R2= H；
Or Ar=Ph, R1=Ph, R2= H；
Or Ar=Ph, R1=Ph, R2 = Me。
3. the synthetic method of four circle heterocyclic rings benzothiophene according to claim 1 or 2 and quinoline compound, feature exist
In: the following steps are included:
(1) 3- thioquinoline -2- ketone is put into dry reaction flask, phosphorus oxychloride reagent is added under room temperature, stirring makes it
Dissolution；The mol ratio of the 3- thioquinoline -2- ketone and phosphorus oxychloride is 0.1-1:1；
(2) it flows back 1-4 hours at a temperature of dissolved solution being heated to 90-110 DEG C；
(3) it after raw material fully reacting, is poured into cold water after reaction solution is cooled to room temperature, then adjusts pH to 10 with ammonium hydroxide,
It is extracted with ethyl acetate 2-3 times, extract liquor is dry with anhydrous sodium sulfate；
(4) target product benzothiophene and quinoline are recrystallized to obtain with n-hexane after extract liquor being concentrated.
4. the synthetic method of four circle heterocyclic rings benzothiophene according to claim 3 and quinoline compound, it is characterised in that: 3-
The mol ratio of thioquinoline -2- ketone and phosphorus oxychloride is 0.5:1.
5. the synthetic method of four circle heterocyclic rings benzothiophene according to claim 3 and quinoline compound, it is characterised in that: anti-
Answering temperature is 100 DEG C, and the reaction time is 2 hours.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87106996A (en) * | 1986-10-17 | 1988-06-15 | 美克德株式会社 | Quinoline compound, their preparation method and with its carcinostatic agent as the active drug component |
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2017
- 2017-07-21 CN CN201710601929.3A patent/CN107325110B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87106996A (en) * | 1986-10-17 | 1988-06-15 | 美克德株式会社 | Quinoline compound, their preparation method and with its carcinostatic agent as the active drug component |
Non-Patent Citations (2)
| Title |
|---|
| Benzothieno[3,2-b]quinolinium and 3-(phenylthio)quinolinium compounds:Synthesis and evaluation against opportunistic fungal pathogens;Comfort A. Boateng et al.;《Bioorganic & Medicinal Chemistry》;20101110;第19卷;458-470 |
| Synthesis and evaluation of isosteres of N-methyl indolo[3,2-b]-quinoline (cryptolepine) as new antiinfective agents;Xue Y. Zhu et al.;《Bioorganic & Medicinal Chemistry》;20061101;第15卷;686-695 |
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