CN109180661A - The chloro- 2-(thienyl -2- base of 6-) quinazoline synthetic method - Google Patents
The chloro- 2-(thienyl -2- base of 6-) quinazoline synthetic method Download PDFInfo
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- CN109180661A CN109180661A CN201811299506.1A CN201811299506A CN109180661A CN 109180661 A CN109180661 A CN 109180661A CN 201811299506 A CN201811299506 A CN 201811299506A CN 109180661 A CN109180661 A CN 109180661A
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- thienyl
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- C07—ORGANIC CHEMISTRY
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses a kind of chloro- 2-(thienyl -2- bases of 6-) synthetic method of quinazoline, comprising the following steps: (2- amino -5- chlorphenyl) methanol, 2- cyano thiophene, catalyst, alkali and solvent is sequentially added in the reactor；Magnetic agitation is reacted in air atmosphere, is sufficiently reacted in oil bath pan.Present invention employs alcohol as the starting material (cheaply, being easily handled and environmentally friendly) for forming C-N key；Inventive process avoids use various oxidants in conventional method and caused by a large amount of by-product problems；Catalyst of the method for the present invention using NNN type pincer metal Ru (II) compound as catalysis reaction, one step of reaction are completed, and the reaction time is substantially reduced, and easy to operate, reaction efficiency is high, meet the requirement of Green Chemistry sustainable development.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of conjunction of the chloro- 2- of 6- (thienyl -2- base) quinazoline
At method.
Background technique
Quinazoline is a kind of extremely important and common nitrogen heterocyclic, and derivative is normally present in various alkaloids
In functional molecular, have a variety of biologies and pharmacological activity: such as anticancer, antimalarial is anti-inflammatory, and antibacterial is anticonvulsion, treating tuberculosis and anti-height
The characteristics such as blood pressure.(Med.Chem.Res.,2013,23,1397.DrugsFuture,2009,34,
618.Eur.J.Med.Chem., 2014,80,447.J.Mol.Struct., 2017,1130,895.) it is being treated due to quinazoline
It is in recent years, also increasingly mature to the research of quinazoline building with the important function played in pharmacology application.
It has been reported that building quinazoline method, largely need the oxidant of equivalent, the substrate of pre- functionalization or outer
Portion's additive, these all do not have environment friendly and Atom economy.(Chem.Commun.2013,49,6439-
644.J.Org.Chem.2016,81,3000-3006.Chem.-Eur.J.2012,18,8882-8885.Org.Lett.2015,
17,3434-3437.) hence it is highly desirable to develop the efficient and sustainable method for synthesizing quinazoline.Here, this laboratory
It has been synthetically prepared bis- (6- methylimidazole simultaneously [1,2-a] pyridine -2- base) the pyridine NNN of the symmetrical 2,6- with pyridine center framework
Type pincer ruthenium (II) compound, the compound have efficiently been catalyzed the anti-of (2- amino -4- chlorphenyl) methanol and hydroxy pyrimidine
It answers.The research that this method synthesizes quinazoline and applies will be significant.
Summary of the invention
Aiming at the problems existing in the prior art, the present invention provides a kind of conjunction of the chloro- 2- of 6- (thienyl -2- base) quinazoline
At method, transition metal pincer catalyst ruthenium (II) compound is used, the reaction time is substantially reduced, has improved reaction effect
Rate.
In order to solve the above technical problems, the invention adopts the following technical scheme:
A kind of synthetic method of the chloro- 2- of 6- (thienyl -2- base) quinazoline, comprising the following steps: in the reactor successively
(2- amino -5- chlorphenyl) methanol, 2- cyano thiophene, catalyst, alkali and solvent is added；Magnetic agitation in air atmosphere, 130
4h is reacted under the conditions of DEG C, after reaction rotary evaporation in vacuo, TLC separation purifies to obtain the chloro- 2- (thiophene of target product 6-
Base -2- base) quinazoline, the structural formula of the chloro- 2- of 6- (thienyl -2- base) quinazoline are as follows:
The reactor is the high-voltage tube of dried and clean, and high-voltage tube uses standard technique, and entire reaction is in air item
It is carried out under part.
The ratio between described amount of substance of (2- amino -5- chlorphenyl) methanol and 2- cyano thiophene is 2:1~1:1.
The catalyst is pincerlike metal Ru (II) compound, and the amount of pincerlike metal Ru (II) compound used is 2- cyanogen
The 1% of the amount of the substance of base thiophene, general structure are as follows:
The ratio between described amount of substance of alkali and 2- cyano thiophene is (0.3-0.6): 1.
The alkali selects potassium tert-butoxide, sodium hydroxide, sodium carbonate, sodium methoxide, potassium phosphate, sodium ethoxide, cesium carbonate, three second
One of amine.
The solvent is the mixture of one or more of acetonitrile, toluene, the tert-butyl alcohol.
Typical synthesis step is as follows: under air atmosphere, a certain amount of (2- amino -5- chlorphenyl) methanol is added, with
2- cyano thiophene, pincerlike ruthenium compound, alkali and the solvent of corresponding amount are added afterwards, and 130 DEG C are reacted 4h in oil bath pan.Through TLC
It determines, the fully reacting of raw material 2- cyano thiophene, rotary evaporation in vacuo, TLC separation purifying calculates the chloro- 2- (thiophene of 6-
Pheno base -2- base) quinazoline yield.
The method of the present invention has the advantages that significant compared with traditional handicraft: (1) being used as present invention employs alcohol and form C-N key
Starting material (cheap, be easily handled and environmental protection)；(2) this method avoids various oxidants are used in conventional method
A large amount of by-product problems caused by and；(3) the method for the present invention is using NNN type pincer metal Ru (II) compound as catalysis reaction
Catalyst, one step of reaction completes, and substantially reduces the reaction time, easy to operate, reaction efficiency is high, and meeting Green Chemistry can hold
The requirement of supervention exhibition.
Specific embodiment
Combined with specific embodiments below, the present invention will be further described.It should be understood that following embodiment is merely to illustrate this
The person skilled in the art of the range of invention and is not intended to limit the present invention, the field can make one according to the content of foregoing invention
A little nonessential modifications and adaptations.
Embodiment 1
In 15ml high-voltage tube, 58.89mg (0.375mmol) (2- amino -5- chlorphenyl) methanol, 27.25mg is added
(0.25mmol) 2- cyano thiophene, 5.1mg (0.3equiv) sodium ethoxide, 2mL toluene, magnetic agitation under air atmosphere, at 130 DEG C
Temperature reacts 4h.It is analyzed through TLC, No Reaction.
Embodiment 2
The synthetic method of the chloro- 2- of the 6- of the present embodiment (thienyl -2- base) quinazoline, steps are as follows:
In 15ml high-voltage tube, 58.89mg (0.375mmol) (2- amino -5- chlorphenyl) methanol, 27.25mg is added
(0.25mmol) 2- cyano thiophene, 1.93mg (1mol%) pincerlike metal Ru (II) compound, 5.1mg (0.3equiv) ethyl alcohol
Sodium, the 2mL tert-butyl alcohol, magnetic agitation under air atmosphere react 4h in 130 DEG C of temperature.It is analyzed through TLC, raw material 2- cyano thiophene is
It is reacted complete.Rotary evaporation in vacuo, TLC separation purifying, the quality of the chloro- 2- of product 6- (thienyl -2- base) quinazoline
For 22.5mg, yield 35%.Product warp1H NMR、13C NMR confirmation.1H NMR (400MHz, CDCl3) δ 9.28 (d, J=
0.5Hz, 1H), 8.14 (dd, J=3.7,1.2Hz, 1H), 7.95 (d, J=9.0Hz, 1H), 7.85 (d, J=2.3Hz, 1H),
7.80 (dd, J=9.0,2.3Hz, 1H), 7.53 (dd, J=5.0,1.2Hz, 1H), 7.21-7.16 (m, 1H) .13C NMR
(101MHz,CDCl3)δ159.6,158.1,149.1,143.4,135.3,132.5,130.4,129.9,129.6,128.5,
126.0,123.7.
Embodiment 3
The synthetic method of the chloro- 2- of the 6- of the present embodiment (thienyl -2- base) quinazoline, steps are as follows:
In 15ml high-voltage tube, 39.26mg (0.25mmol) (2- amino -5- chlorphenyl) methanol, 27.25mg
(0.25mmol) 2- cyano thiophene, 1.93mg (1mol%) pincerlike metal Ru (II) compound, 16.83mg (0.6equiv) tertiary fourth
Magnetic agitation under the mixed solution of potassium alcoholate, 2mL acetonitrile and the tert-butyl alcohol, air atmosphere reacts 4h in 130 DEG C of temperature.Through TLC points
Analysis, the fully reacting of raw material 2- cyano thiophene.Rotary evaporation in vacuo, TLC separation purifying, the chloro- 2- (thiophene of product 6-
Base -2- base) quinazoline be 40.3mg, yield 67%.
Embodiment 4
The synthetic method of the chloro- 2- of the 6- of the present embodiment (thienyl -2- base) quinazoline, steps are as follows:
In 15ml high-voltage tube, 78.51mg (0.50mmol) 2- amino -4- chlorphenyl is added) methanol, 27.25mg
(0.25mmol) 2- cyano thiophene, 1.93mg (1mol%) pincerlike metal Ru (II) compound, 6.0mg (0.6equiv) hydroxide
Sodium, magnetic agitation under 2mL toluene, air atmosphere react 4h in 130 DEG C of temperature.It is analyzed through TLC, raw material 2- cyano thiophene is
Fully reacting.Rotary evaporation in vacuo, TLC separation purifying, the chloro- 2- of product 6- (thienyl -2- base) quinazoline are
39.7mg, yield 65%.
Embodiment 5
The synthetic method of the chloro- 2- of the 6- of the present embodiment (thienyl -2- base) quinazoline, steps are as follows:
In 15ml high-voltage tube, 58.89mg (0.375mmol) (2- amino -5- chlorphenyl) methanol, 27.25mg is added
(0.25mmol) 2- cyano thiophene, 1.96mg (1mol%) pincerlike metal Ru (II) compound, 16.83mg (0.6equiv) tertiary fourth
Potassium alcoholate, magnetic agitation under 2ml tert-butyl alcohol air atmosphere react 4h in 130 DEG C of temperature.It is analyzed through TLC, raw material 2- cyano thiophene
Fully reacting.Rotary evaporation in vacuo, TLC separation purifying, the chloro- 2- of product 6- (thienyl -2- base) quinazoline are
46.8mg, yield 76%.
Basic principles and main features and advantages of the present invention of the invention have been shown and described above.The skill of the industry
Art personnel it should be appreciated that the present invention is not limited to the above embodiments, the above embodiments and description only describe
The principle of the present invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these
Changes and improvements all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and
Its equivalent thereof.
Claims (7)
1. a kind of synthetic method of the chloro- 2- of 6- (thienyl -2- base) quinazoline, which comprises the following steps: reacting
(2- amino -5- chlorphenyl) methanol, 2- cyano thiophene, catalyst, alkali and solvent is sequentially added in device；Magnetic force stirs in air atmosphere
Mix, react 4h under the conditions of 130 DEG C, after reaction rotary evaporation in vacuo, TLC separation purify target product 6- is chloro-
2- (thienyl -2- base) quinazoline, the structural formula of the chloro- 2- of 6- (thienyl -2- base) quinazoline are as follows:
2. the synthetic method of the chloro- 2- of 6- (thienyl -2- base) quinazoline according to claim 1, it is characterised in that: described
Reactor be dried and clean high-voltage tube, and entire reaction is carried out under air conditions.
3. the synthetic method of the chloro- 2- of 6- (thienyl -2- base) quinazoline according to claim 1, it is characterised in that: described
(2- amino -5- chlorphenyl) methanol and the ratio between the amount of substance of 2- cyano thiophene be 2:1~1:1.
4. the synthetic method of the chloro- 2- of 6- (thienyl -2- base) quinazoline according to claim 1, it is characterised in that: described
Catalyst is pincerlike metal Ru (II) compound, and the amount of pincerlike metal Ru (II) compound used is the substance of 2- cyano thiophene
Amount 1%, it is described pincer metal Ru (II) compound general structure are as follows:
5. the synthetic method of the chloro- 2- of 6- (thienyl -2- base) quinazoline according to claim 1, it is characterised in that: described
Alkali and the ratio between the amount of substance of 2- cyano thiophene be (0.3-0.6): 1.
6. the synthetic method of the chloro- 2- of 6- (thienyl -2- base) quinazoline according to claim 1, it is characterised in that: described
Alkali select potassium tert-butoxide, sodium hydroxide, sodium carbonate, sodium methoxide, potassium phosphate, sodium ethoxide, cesium carbonate, one of triethylamine.
7. the synthetic method of the chloro- 2- of 6- (thienyl -2- base) quinazoline according to claim 1, it is characterised in that: institute
The solvent stated is the mixture of one or more of acetonitrile, toluene, the tert-butyl alcohol.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113861119A (en) * | 2021-11-23 | 2021-12-31 | 河北师范大学 | Method for synthesizing quinoline and quinazoline compounds under catalysis of cobalt |
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| CN105327703A (en) * | 2014-08-08 | 2016-02-17 | 中国科学技术大学 | Preparation method for gold nanometer catalyst, and obtained catalyst product and application thereof |
| CN105732619A (en) * | 2016-02-03 | 2016-07-06 | 华南理工大学 | Synthesizing method of 5,6,7,8-tetrahydropyridino-[2,3-d]pyrimidine compound |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113861119A (en) * | 2021-11-23 | 2021-12-31 | 河北师范大学 | Method for synthesizing quinoline and quinazoline compounds under catalysis of cobalt |
| CN113861119B (en) * | 2021-11-23 | 2023-11-24 | 河北师范大学 | Method for synthesizing quinoline and quinazoline compounds by cobalt catalysis |
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Application publication date: 20190111 |