CN111377872A - Synthesis method of 2-chloro-4-phenylbenzoquinazoline - Google Patents
Synthesis method of 2-chloro-4-phenylbenzoquinazoline Download PDFInfo
- Publication number
- CN111377872A CN111377872A CN201811637090.XA CN201811637090A CN111377872A CN 111377872 A CN111377872 A CN 111377872A CN 201811637090 A CN201811637090 A CN 201811637090A CN 111377872 A CN111377872 A CN 111377872A
- Authority
- CN
- China
- Prior art keywords
- reaction
- phenyl
- chloro
- phenylbenzoquinazoline
- tetrahydrobenzoquinazolin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
Abstract
The invention discloses a synthetic method of 2-chloro-4-phenylbenzoquinazoline, belonging to the field of organic chemical synthesis, and the 2-chloro-4-phenylbenzoquinazoline is obtained by taking 1-tetralone, benzaldehyde and urea as raw materials and performing three-step reactions including cyclization, oxidation and chlorination in a Bijieli reaction. The invention has low requirements on equipment and reaction conditions, easily obtained raw materials, low cost and short process period, and can greatly improve the synthesis efficiency and economic benefit.
Description
Technical Field
The invention relates to a synthetic method of 2-chloro-4-phenylbenzoquinazoline, and belongs to the field of chemical synthesis.
Background art:
the 2-chloro-4-phenylbenzoquinazoline is a fine chemical raw material, is widely applied to synthesis of heterocyclic compounds, is an important OLED intermediate discovered in recent years, has a large market potential internationally as the OLED intermediate, and is produced less domestically.
Currently, the 2-chloro-4-phenylbenzoquinazoline synthesis methods can be broadly divided into two categories: (1) the method comprises the following steps of performing amination, ring closing and chlorination by using 2-benzoyl-1-naphthol as a raw material to obtain a final product, wherein the amination reaction uses expensive 2-bromoisobutyramide, the amination reaction comprises electrophilic substitution and rearrangement two-step reaction, the reaction time is long, the biggest problem is that the 2-benzoyl-1-naphthol raw material is difficult to obtain, the para-position of hydroxyl can be reached with great probability by adopting naphthol and benzoyl to perform paracorporeation acylation reaction in a synthetic route, the ortho-position product is difficult to obtain, the required reaction conditions are harsh, a large amount of acid water is generated by aftertreatment, and the yield is not high; (2) the 2-chloro-4-phenylbenzoquinazoline is obtained by coupling 2, 4-dichlorobenzo [ h ] quinazoline and phenylboronic acid or phenylboronic acid pinacol ester, the yield is 50-60%, in the method, the 2, 4-dichlorobenzo [ h ] quinazoline raw material is expensive and difficult to obtain, a palladium catalyst is needed, and the production cost is high.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the synthetic method of the 2-chloro-4-phenylbenzoquinazoline, which has the advantages of low cost, simple operation, proper yield, mild reaction conditions, less reaction byproducts, high reaction yield and higher economic benefit.
A synthetic method of 2-chloro-4-phenylbenzoquinazoline adopts the following steps:
(1) provides a method for synthesizing 4-phenyl-3, 4, 5, 6-tetrahydrobenzoquinazolin-2 (1H) ketone,
(2) oxidizing 4-phenyl-3, 4, 5, 6-tetrahydrobenzoquinazolin-2 (1H) one with DDQ to give 4-phenyl-1H-benzo [ H ] quinazolin-2-one,
(3) and carrying out reflux reaction on phosphorus oxychloride to obtain the most target product 2-chloro-4-phenylbenzoquinazoline.
The reaction process in the step (2) is that 4-phenyl-3, 4, 5, 6-tetrahydrobenzoquinazoline-2 (1H) ketone, DDQ and o-dichlorobenzene react at 160-165 ℃, when the reaction is completely cooled, n-hexane is added into the system, crystals are separated out, and the mixture of the yellow solid product 4-phenyl-1H-benzo [ H ] quinazoline-2-ketone and partial residue is obtained by filtering and is directly used in the step (3).
And (3) heating the mixture obtained in the step (2) and phosphorus oxychloride to a temperature of 100-110 ℃ for reflux, concentrating after complete reaction, cooling, adding toluene into the system, passing through silica gel to obtain a light yellow solution, and concentrating the filtrate to obtain a target product.
And (3) further purifying the target product obtained by concentration, and adding n-hexane into the concentrate to elute a white solid product, namely the 2-chloro-4-phenylbenzoquinazoline.
The preparation method of the step (1) comprises the steps of heating tetralone, benzaldehyde, urea, trimethylchlorosilane, sodium iodide and ethanol for reflux, cooling after complete reaction and filtering to obtain a white solid 4-phenyl-3, 4, 5, 6-tetrahydrobenzoquinazoline-2 (1H) ketone.
The tetralone, the benzaldehyde and the urea react in equivalent, and the molar equivalent of the trimethylchlorosilane and the sodium iodide is 1.2.
In the step (1), 1-tetralone, benzaldehyde, urea and ethanol are mixed, and trimethylchlorosilane and sodium iodide are added under stirring to be heated and refluxed.
And (2) eluting the solid substance obtained by filtering in the step (1) by adopting water and water alcohol to obtain a white-like solid.
Compared with the prior art, the method adopts 1-tetralone, benzaldehyde and urea as raw materials, adopts a biginel one-step ring closure method to close rings to obtain the key intermediate 4-phenyl-1H-benzo [ H ] quinazoline-2-one, has mild reaction conditions and simple operation, then oxidizes and chlorinates the key intermediate to obtain the product 2-chloro-4 phenyl benzo quinazoline, has short period of the whole process flow and non-harsh reaction conditions, and can obtain white powder with the purity of more than 99.5 percent after being recrystallized by adopting tetrahydrofuran and normal hexane.
The invention has the beneficial effects that:
1. the invention adopts a one-step cyclization method of benraline to carry out ring closure to obtain a key intermediate 4-phenyl-1H-benzo [ H ] quinazoline-2-ketone, the reaction condition is mild, the reaction speed is high, all raw materials are easy to obtain, and the product obtained after the reaction can be better crystallized, is beneficial to purification and is easy for industrial popularization;
2. the method adopts 2, 3-dichloro-5, 6-dicyan p-benzoquinone (DDQ) to oxidize the by-products of the nitrogen heterocycles and the hydrogen on the benzene rings, can directly carry out the next chlorination reaction without treatment, concentrates most phosphorus oxychloride after the reaction is finished, then adopts toluene to dissolve, washes and passes through silica gel, the residual DDQ and the by-products thereof can be well filtered (used as waste solids together with the silica gel), then concentrates the mother liquor, and recrystallizes to obtain the product with the purity of 99.5 percent, the operation process is simple, the efficiency is high, the cost of the used raw materials is low, and the method is favorable for industrial popularization;
3. according to the invention, residual DDQ is not treated, and a by-product with poor solubility is obtained after chlorination reaction is directly carried out, and can be well removed by adopting a silica gel mode, no wastewater is generated, the post-treatment process is greatly simplified, and the economic benefit is stronger;
4. the invention optimizes the reaction process and reaction conditions, can effectively shorten the reaction time, reduce the generation of reaction byproducts, improve the reaction yield and have higher economic benefit.
Detailed Description
The following is a detailed description of the embodiments of the present invention, which is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments. The experimental protocol, in which the specific conditions are not specified in the examples, is generally carried out according to the conventional conditions or conditions recommended by the manufacturer.
Example 1
A synthetic method of 2-chloro-4-phenylbenzoquinazoline comprises the following steps:
the first step is as follows: 4-phenyl-3, 4, 5, 6-tetrahydrobenzoquinazolin-2 (1H) ones
Adding 10.0g of 1-tetralone, 8.0g of benzaldehyde, 4.9g of urea and 150mL of ethanol into a 500mL container, adding 8.9g of trimethylchlorosilane and 12.3g of sodium iodide while stirring, heating to 80 ℃, reacting for 2 hours, cooling to room temperature after reaction, filtering, eluting the solid by using a small amount of water and ethanol to obtain 11.8g of off-white solid 4-phenyl-3, 4, 5, 6-tetrahydrobenzoquinazolin-2 (1H) ketone with the yield of 62.42%;
the second step is that: synthesis of 4-phenyl-1H-benzo [ H ] quinazolin-2-one:
adding 11.8g of 4-phenyl-3, 4, 5, 6-tetrahydrobenzoquinazolin-2 (1H) ketone synthesized in the first step, 18.9g of DDQ and 60mL of o-dichlorobenzene into a 250mL container, heating to 70-75 ℃ for reaction for 30min, adding 10.0g of DDQ, heating to 160-165 ℃ for reaction for 2H, adding 10mL of n-hexane into the system after the reaction is completely cooled to 60-65 ℃, continuously cooling for crystallization to room temperature for crystallization for 2H after the addition is finished, and filtering to obtain a mixture 36.2g of a yellow solid which is a product of 4-phenyl-1H-benzo [ H ] quinazolin-2-one and part of residues;
the third step: synthesis of 2-chloro-4-phenylbenzoquinazoline:
adding 36.2g of the mixture obtained in the second step and 180ml of phosphorus oxychloride into a 500ml container, heating the system to 100-110 ℃, carrying out reflux reaction for 3h, concentrating the reaction solution until no liquid flows out, cooling the system to 70-80 ℃, adding 500ml of toluene into the system, continuously cooling to room temperature after adding, passing through silica gel to obtain a light yellow solution, concentrating the filtrate until a small amount of solvent remains, adding n-hexane into the system, and eluting 9.3g of a white solid product, namely 2-chloro-4-phenylbenzoquinazoline.
Example 2
A synthetic method of 2-chloro-4-phenylbenzoquinazoline comprises the following steps:
the first step is as follows: 4-phenyl-3, 4, 5, 6-tetrahydrobenzoquinazolin-2 (1H) ones
Adding 10.0g of 1-tetralone, 8.0g of benzaldehyde, 4.9g of urea and 150mL of acetonitrile into a 500mL container, adding 8.9g of trimethylchlorosilane and 12.3g of sodium iodide while stirring, heating to 80 ℃, reacting for 2H, cooling to room temperature after reaction, filtering, eluting the solid by using a small amount of water and ethanol to obtain 9.5g of off-white solid 4-phenyl-3, 4, 5, 6-tetrahydrobenzoquinazolin-2 (1H) ketone with the yield of 50.26%;
the second step is that: synthesis of 4-phenyl-1H-benzo [ H ] quinazolin-2-one:
adding 11.8g of 4-phenyl-3, 4, 5, 6-tetrahydrobenzoquinazolin-2 (1H) ketone synthesized in the first step, 18.9g of DDQ and 60mL of o-dichlorobenzene into a 250mL container, heating to 70-75 ℃ for reaction for 30min, adding 10.0g of DDQ, heating to 160-165 ℃ for reaction for 2H, adding 10mL of n-hexane into the system after the reaction is completely cooled to 60-65 ℃, continuously cooling for crystallization to room temperature for crystallization for 2H after the addition is finished, and filtering to obtain a mixture of 33.4g of 4-phenyl-1H-benzo [ H ] quinazolin-2-one and partial residues as a yellow solid;
the third step: synthesis of 2-chloro-4-phenylbenzoquinazoline:
adding 36.2g of the mixture obtained in the second step and 180ml of phosphorus oxychloride into a 500ml container, heating the system to 100-110 ℃, carrying out reflux reaction for 3h, concentrating the reaction solution until no liquid flows out, cooling the system to 70-80 ℃, adding 500ml of toluene into the system, continuously cooling to room temperature after adding, passing through silica gel to obtain a light yellow solution, concentrating the filtrate until a small amount of solvent remains, adding n-hexane into the system, and eluting 6.1g of a white solid product, namely 2-chloro-4-phenylbenzoquinazoline.
Example 3
The first step is as follows: 4-phenyl-3, 4, 5, 6-tetrahydrobenzoquinazolin-2 (1H) ones
Adding 10.0g of 1-tetralone, 8.0g of benzaldehyde, 4.9g of urea and 150mL of ethanol into a 500mL container, adding 10.4g of trimethylchlorosilane and 14.4g of sodium iodide while stirring, heating to 80 ℃ for reaction for 2H, cooling to room temperature after the reaction, filtering, eluting the solid by using a small amount of water and ethanol to obtain 11.2g of off-white solid 4-phenyl-3, 4, 5, 6-tetrahydrobenzoquinazolin-2 (1H) ketone with the yield of 59.25%;
the second step is that: synthesis of 4-phenyl-1H-benzo [ H ] quinazolin-2-one:
adding 11.8g of 4-phenyl-3, 4, 5, 6-tetrahydrobenzoquinazolin-2 (1H) ketone synthesized in the first step, 18.9g of DDQ and 60mL of o-dichlorobenzene into a 250mL container, heating to 70-75 ℃ for reaction for 30min, adding 10.0g of DDQ, heating to 160-165 ℃ for reaction for 2H, adding 10mL of n-hexane into the system after the reaction is completely cooled to 60-65 ℃, continuously cooling for crystallization to room temperature for crystallization for 2H after the addition is finished, and filtering to obtain 34.6g of a mixture of a yellow solid product, namely 4-phenyl-1H-benzo [ H ] quinazolin-2-one, and partial residues;
the third step: synthesis of 2-chloro-4-phenylbenzoquinazoline:
adding 36.2g of the mixture obtained in the second step and 180ml of phosphorus oxychloride into a 500ml container, heating the system to 100-110 ℃, carrying out reflux reaction for 3h, concentrating the reaction solution until no liquid flows out, cooling the system to 70-80 ℃, adding 500ml of toluene into the system, continuously cooling to room temperature after adding, passing through silica gel to obtain a light yellow solution, concentrating the filtrate until a small amount of solvent remains, adding n-hexane into the system, and eluting 8.9g of a white solid product, namely 2-chloro-4-phenylbenzoquinazoline.
The yield comparisons after the condition screening mainly for the first step yield according to the examples are as follows:
the method provided by the embodiment of the invention has the advantages that the yield, the process simplicity and the cost control of the 2-chloro-4-phenylbenzoquinazoline are obviously improved, and the economic benefit is higher.
The above description is only a preferred embodiment of the present invention, and for those skilled in the art, the present invention should not be limited by the description herein, since various changes and modifications can be made in the details of the embodiment and the application range according to the spirit of the present invention.
Claims (8)
1. A synthetic method of 2-chloro-4-phenylbenzoquinazoline adopts the following steps:
(1) provides a method for synthesizing 4-phenyl-3, 4, 5, 6-tetrahydrobenzoquinazolin-2 (1H) ketone,
(2) oxidizing 4-phenyl-3, 4, 5, 6-tetrahydrobenzoquinazolin-2 (1H) one with DDQ to give 4-phenyl-1H-benzo [ H ] quinazolin-2-one,
(3) and carrying out reflux reaction on phosphorus oxychloride to obtain the most target product 2-chloro-4-phenylbenzoquinazoline.
2. The synthesis method according to claim 1, wherein the reaction process in the step (2) is to react 4-phenyl-3, 4, 5, 6-tetrahydrobenzoquinazolin-2 (1H) one, DDQ and o-dichlorobenzene at 160-165 ℃, cool down after the reaction is completed, add n-hexane into the system, separate out crystals, filter to obtain a mixture of yellow solid product 4-phenyl-1H-benzo [ H ] quinazolin-2-one and partial residue, and directly use the mixture in the step (3).
3. The synthesis method according to claim 2, wherein the mixture obtained in the step (2) and phosphorus oxychloride are heated to 100-110 ℃ for reflux, and after complete reaction, the mixture is concentrated and cooled, toluene is added into the system, silica gel is added to obtain a light yellow solution, and the filtrate is concentrated to obtain the target product.
4. The method of claim 3, wherein the concentration to obtain the target product requires further purification, and n-hexane is added to the concentrate to elute the white solid product 2-chloro-4-phenylbenzoquinazoline.
5. The synthesis method according to any one of claims 1 to 4, wherein the step (1) is carried out by heating tetralone, benzaldehyde, urea, trimethylchlorosilane, sodium iodide and ethanol under reflux, cooling after the reaction is completed and filtering to obtain the white-like solid 4-phenyl-3, 4, 5, 6-tetrahydrobenzoquinazolin-2 (1H) one.
6. The synthesis method of claim 5, wherein tetralone, benzaldehyde and urea react in an equivalent manner, and the addition amount of trimethylchlorosilane and sodium iodide is 1.2 molar equivalents.
7. The synthesis method according to claim 5, wherein in step (1), 1-tetralone, benzaldehyde, urea and ethanol are mixed, and trimethylchlorosilane and sodium iodide are added under stirring and heated to reflux.
8. The method of claim 7, wherein the solid material obtained by filtering in step (1) is eluted with water and hydroalcoholic to obtain a white-like solid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811637090.XA CN111377872A (en) | 2018-12-29 | 2018-12-29 | Synthesis method of 2-chloro-4-phenylbenzoquinazoline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811637090.XA CN111377872A (en) | 2018-12-29 | 2018-12-29 | Synthesis method of 2-chloro-4-phenylbenzoquinazoline |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111377872A true CN111377872A (en) | 2020-07-07 |
Family
ID=71220863
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811637090.XA Pending CN111377872A (en) | 2018-12-29 | 2018-12-29 | Synthesis method of 2-chloro-4-phenylbenzoquinazoline |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111377872A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103298816A (en) * | 2010-12-17 | 2013-09-11 | 内尔维阿诺医学科学有限公司 | Substituted pyrazolo-quinazoline derivatives as kinase inhibitors |
| US20180026203A1 (en) * | 2015-02-13 | 2018-01-25 | Idemitsu Kosan Co., Ltd. | Compound, material for organic electroluminescent element, ink composition, organic electroluminescent element, and electronic device |
-
2018
- 2018-12-29 CN CN201811637090.XA patent/CN111377872A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103298816A (en) * | 2010-12-17 | 2013-09-11 | 内尔维阿诺医学科学有限公司 | Substituted pyrazolo-quinazoline derivatives as kinase inhibitors |
| US20180026203A1 (en) * | 2015-02-13 | 2018-01-25 | Idemitsu Kosan Co., Ltd. | Compound, material for organic electroluminescent element, ink composition, organic electroluminescent element, and electronic device |
Non-Patent Citations (4)
| Title |
|---|
| GOWRAVARAM SABITHA ET AL.: "Iodotrimethylsilane-Accelerated One-Pot Synthesis of 5-Unsubstituted 3,4-Dihydropyrimidin-2(1H)-ones: A Novel Procedure for the Biginelli-Like Cyclocondensation Reaction at Room Temperature", 《HELVETICA CHIMICA ACTA》 * |
| MARYAM MIRZA-AGHAYAN ET AL.: "Cheap and Efficient Protocol for the Synthesis of Tetrahydroquinazolinone, Dihydropyrimidinone, and Pyrimidinone Derivatives", 《SYNTHETIC COMMUNICATIONS》 * |
| N.R.EL-RAYYES ET AL.: "Heterocycles. XIII. N1s orbital binding energies of some quinazolines and pyrimidines by XPS", 《JOURNAL OF HETEROCYCLIC CHEMISTRY》 * |
| V. P. MAMAEV AND V. F. SEDOVA: "Pyrimidines. III. Dehydrogenation of 4-phenylbenzo[h]quinazoline derivatives", 《KHIMIYA GETEROTSIKLICHESKIKH SOEDINENII》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102311392B (en) | Synthetic method of azoxystrobin and special intermediate for synthesis | |
| CN109503513B (en) | One-pot synthesis method of febuxostat intermediate | |
| CN108395381B (en) | Synthesis method of 1, 4-diamino anthraquinone leuco body | |
| CN111377872A (en) | Synthesis method of 2-chloro-4-phenylbenzoquinazoline | |
| TW585855B (en) | A novel production method for maleimides | |
| CN111454223B (en) | Synthetic method of 2, 3-dihydroxy-6-chloroquinoxaline | |
| CN105348285B (en) | Low-cost and high-yield adenine preparation method | |
| CN111116478B (en) | Preparation method of antibiotic virginiamycin intermediate for livestock | |
| CN110903254B (en) | Synthetic method of heterocyclic intermediate applied to JAK inhibitor drugs | |
| CN108033918B (en) | Synthesis method of photoelectric material intermediate 2-chloro-4-phenylbenzo [ h ] quinazoline | |
| CN110092751B (en) | Synthesis method of 2-alkyl quinoline | |
| CN115677707B (en) | Method for preparing 2,4,6, 8-tetrahydroxypyrimido [5,4-d ] pyrimidine by diaminomaleonitrile method | |
| CN108976200B (en) | Method for preparing pimobendan from side product of pimobendan synthesis | |
| CN108503580A (en) | A kind of preparation method of Eliquis intermediate | |
| CN112645854B (en) | Refining method of Apremilast intermediate | |
| KR20180011830A (en) | New method for preparation of chromanone derivatives | |
| CN107652269A (en) | Methanesulfonic acid fluorine imatinib purification of intermediate method | |
| CN111004250B (en) | Synthetic method of 1, 4-epoxy-2, 3-dicyano-1, 2,3, 4-tetrahydronaphthalene | |
| CN110372594B (en) | Synthesis method of 1, 3-dimethyl-1H-pyrazole-4-formic acid | |
| CN114920635B (en) | Preparation method of 4-hydroxy-1-indenone | |
| CN113773235B (en) | Synthesis method of clorsulon | |
| CN117624009A (en) | Continuous synthesis method of JAK inhibitor drug heterocyclic intermediate | |
| CN106117190B (en) | A kind of synthetic method of times of good fortune Pulan | |
| CN107674052B (en) | Synthesis method of vilazodone intermediate 5- (1-piperazinyl) -2-benzofuran-2-carboxylic acid ethyl ester | |
| CN116239577A (en) | Method for preparing cudexestat |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200707 |