CN112624984B - 4-thio quinazoline diketone derivative and preparation method thereof - Google Patents

4-thio quinazoline diketone derivative and preparation method thereof Download PDF

Info

Publication number
CN112624984B
CN112624984B CN202011553047.2A CN202011553047A CN112624984B CN 112624984 B CN112624984 B CN 112624984B CN 202011553047 A CN202011553047 A CN 202011553047A CN 112624984 B CN112624984 B CN 112624984B
Authority
CN
China
Prior art keywords
thioquinazolinedione
oxo
aminobenzonitrile
reaction
derivative
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.)
Active
Application number
CN202011553047.2A
Other languages
Chinese (zh)
Other versions
CN112624984A (en
Inventor
竺宁
王兆阳
解瑞俊
洪海龙
韩利民
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Inner Mongolia University of Technology
Original Assignee
Inner Mongolia University of Technology
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Inner Mongolia University of Technology filed Critical Inner Mongolia University of Technology
Priority to CN202011553047.2A priority Critical patent/CN112624984B/en
Publication of CN112624984A publication Critical patent/CN112624984A/en
Application granted granted Critical
Publication of CN112624984B publication Critical patent/CN112624984B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a 4-thio quinazoline diketone derivative and a preparation method thereof. The structural formula of the 4-thioquinazolinedione derivative is as follows:
Figure DDA0002857576550000011
the preparation method comprises the following steps: mixing o-aminobenzonitrile, inorganic sulfide and organic solvent, charging CO2And carrying out reaction to obtain the 4-thioquinazoline diketone derivative. CO related to the invention2The activating agent is inorganic sulfide, and is low in price and easy to obtain; high reaction efficiency and wide application value.

Description

4-thio quinazoline diketone derivative and preparation method thereof
Technical Field
The invention relates to the technical field of chemical industry and medicine, in particular to a 4-thioquinazolinedione derivative and a preparation method thereof.
Background
In recent years, the emission of large amounts of domestic and industrial waste gases has led to the emission of CO in the atmosphere2The concentration is gradually increased. CO 22As one of the main components of greenhouse gas, the greenhouse effect is more serious, and the life of people is seriously influenced. Albeit CO2As a major component of greenhouse gases, some negative effects are caused, but it also has many non-negligible advantages, such as: the composite material is cheap, economical, nontoxic, environment-friendly and non-flammable, and can be used as an important renewable C1 module in organic synthesis and the like. CO 22The carbon-carbon composite material consists of two C ═ O bonds, the bond length of the C ═ O is about 116pm, the bond energy is relatively large, and therefore the carbon-carbon composite material shows inherent thermodynamic stability and kinetic inertia, and therefore CO (carbon monoxide) is prepared2The utilization of (c) is still a difficult and long-standing task.
With CO2The capture and utilization (CCU) strategy was implemented by converting them by the CCU method into organic compounds or energy carriers with high added value (dimethyl carbonate, cyclic carbonates, urethanes, polycarbonates, formic acid, N' -disubstituted ureas, 5-aryl-2-oxazolidinones, α, β -unsaturated ketones, benzimidazoles, formamidine derivatives, methyl formate, quinazolinediones, etc.).
In the above-mentioned utilization of CO2In the synthesis of high-value compounds, the quinazolinedione compounds are important medical intermediates and key raw materials for synthesizing the zenarestat, the prazosin hydrochloride and the doxazosin. Has anticancer, antihypertensive, and diabetes treating effects. Methods for the synthesis of quinazolinedionesThe method mainly comprises a synthetic method for efficiently constructing the quinazolinedione by using o-aminobenzonitrile and carbon dioxide under different catalyst conditions. The quinazoline diketone compound has 4 substitutable positions on the benzene ring, and different substitution sites and substituents, so that the quinazoline diketone compound has wide biological activity. Research and development on quinazoline diketone derivatives become one of the hotspots of research on pesticides and medicines at present.
Because the oxygen atoms and the sulfur atoms on the 2,4 sites are positioned in the same main group, and the number of outer electrons is equal, the sulfur atoms replace the oxygen atoms to obtain the isosteric thioquinazolinedione of the quinazolinedione, and the isosteric thioquinazolinedione has similar physical and chemical properties with the quinazolinedione and can generate similar or related biological activity. Therefore, the thioquinazoline diketone compound probably has biological activity similar to that of resisting cancer, resisting hypertension and treating diabetes.
Therefore, the research and development of an economic, green and environment-friendly synthetic method of thioquinazolinedione is a technical problem to be solved urgently at present.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a 4-thioquinazolinedione derivative and a preparation method thereof. The invention utilizes the o-aminobenzonitrile and the carbon dioxide to synthesize the thioquinazolinedione, and a sulfur source is required to participate in the reaction in the process, so that a proper sulfur source needs to be screened out. The inventor finds out through continuous exploration and optimization that: the inorganic sulfide may be reacted with CO2Construction of Monothiocarbonic acid in an activated State to activate CO2The inorganic sulfide also has the advantages of low price and easy availability, which makes the research scheme have high application value, so the inorganic sulfide is selected as the reactant and the CO2Activating reagent of (2) for promoting the reaction of thioo-aminobenzonitrile with CO2The reaction produces a thioquinazolinedione.
In summary, the inorganic sulfides used in the present invention have a dual function, namely as CO2The activator also serves as a sulfur source to participate in the reaction, and provides a novel method for synthesizing the 4-thioquinazoline diketone derivative by utilizing the o-aminobenzonitrile and the carbon dioxideA new route.
One of the objects of the present invention is to provide a 4-thioquinazolinedione derivative.
The structural formula of the 4-thioquinazolinedione derivative is as follows:
Figure BDA0002857576540000021
r is H, F, Cl, Br, CF mono-or polysubstituted at the ortho, meta or para positions of amino3、NO2、C1-8Alkyl radical, C1-8Alkoxy or C1-8One or more sulfonyl groups;
r is preferably F, Cl, Br, CF at the 5-position3、NO2、C1-8Alkyl radical, C1-8Alkoxy, F, Cl, Br, CF in position 63、OCH3、C2-8Alkyl radical, C2-8Alkoxy, Cl, Br, CF in position 73、NO2、 C1-8Alkyl radical, C2-8Alkoxy, F, Cl, Br, CF in position 83、NO2、C1-8Alkyl radical, C1-8An alkoxy group.
More preferably, the 4-thioquinazolinedione derivative is:
6-fluoro-2-oxo-4-thioquinazolinedione, which has the structural formula:
Figure BDA0002857576540000031
6-bromo-2-oxo-4-thioquinazolinedione, having the structural formula:
Figure BDA0002857576540000032
7-trifluoromethyl-2-oxo-4-thioquinazolinedione, which has the structural formula:
Figure BDA0002857576540000033
7-chloro-2-oxo-4-thioquinazolinedione, having the structural formula:
Figure BDA0002857576540000034
7-methyl-2-oxo-4-thioquinazolinedione, which has the structural formula:
Figure BDA0002857576540000035
5-fluoro-2-oxo-4-thioquinazolinedione, having the structural formula:
Figure BDA0002857576540000041
6-trifluoromethyl-2-oxo-4-thioquinazolinedione, which has the structural formula:
Figure BDA0002857576540000042
the invention also aims to provide a preparation method of the 4-thioquinazolinedione derivative.
The method comprises the following steps:
mixing o-aminobenzonitrile, inorganic sulfide and organic solvent, charging CO2Reacting to obtain the 4-sulfo-quinazoline diketone derivative;
charging CO2Then, CO in the reaction kettle2The pressure of (2) is 3-6 MPa;
the reaction temperature is 90-130 ℃; the reaction time is 8-24 h.
The structure of the o-aminobenzonitrile is as follows:
Figure BDA0002857576540000043
r is amino ortho-position, meta-position or para-positionH, F, Cl, Br, CH, mono-or polysubstituted in position3、CF3、 OCH3、NO2、C1-8Alkyl radical, C1-8Alkoxy or C1-8One or more sulfonyl groups.
R is preferably F, Cl, Br, CF at the 5-position3、NO2、C1-8Alkyl radical, C1-8Alkoxy, F, Cl, Br, CF in position 63、OCH3、C2-8Alkyl radical, C2-8Alkoxy, Cl, Br, CF in position 73、NO2、 C1-8Alkyl radical, C2-8Alkoxy, F, Cl, Br, CF in position 83、NO2、C1-8Alkyl radical, C1-8An alkoxy group.
In a preferred embodiment of the present invention,
the inorganic sulfide sulfur is NaSH and Na2S·9H2O, KHS;
in a preferred embodiment of the present invention,
the organic solvent is at least one of methanol, dimethyl sulfoxide, N-methyl pyrrolidone and N, N-dimethylformamide.
In a preferred embodiment of the present invention,
the molar ratio of the o-aminobenzonitrile to the inorganic sulfide is 1: 2-3; preferably 1: 2-3;
the molar ratio of o-aminobenzonitrile to carbon dioxide is 1: 10-30;
in a preferred embodiment of the present invention,
the reaction temperature is 100-120 ℃;
the reaction time is 16-24 h.
The reaction temperature is a key factor influencing the generation of the thioquinazolinedione, the reaction can be converted into the thioquinazolinedione only when the reaction temperature reaches above 90 ℃, the o-aminobenzonitrile is difficult to be converted into the thioquinazolinedione when the reaction temperature is lower than 90 ℃, the reaction reaches the optimal temperature for generating the thioquinazolinedione when the reaction temperature reaches 100 ℃, and the thioquinazolinedione can be obtained with the yield of above 90%.
CO2The pressure of (A) is 3-6 MPa, when CO is present2Pressure of (3) in this range, CO2Can react with trace water in the system to form carbonic acid to provide hydrogen protons to promote the reaction, and only needs a small amount of CO2Because the protons in this process originate from H in the system2O，CO2In this step only as a catalyst promoter, after which CO2Can also be used as a carbonylation reagent to participate in the carbonylation and cyclization steps, thereby participating in the generation process of the target product as a reactant. Since 1 mole of CO needs to be incorporated per 1 mole of thioquinazolinedione produced2Thus CO2The charging pressure of (A) will influence the CO2In the amount of CO2When the charged amount of the organic solvent is 1 or more times equivalent by mol to the charged amount of the o-aminobenzonitrile, CO2The pressure of (A) is not taken as a key factor influencing the reaction, but the reaction temperature is taken as a key factor influencing the reaction progress, but with CO2The filling amount in the field is increased continuously, the pressure of the reaction system is increased, the collision probability among molecules in the system is increased, and therefore, the CO is increased2The amount of (2) is effective in promoting the reaction.
Reaction temperature and CO2The charging pressure of (A) can influence the generation of the thioquinazolinedione, but the reaction temperature is a key factor influencing the generation of the thioquinazolinedione, and when the reaction temperature is lower than 90 ℃, even though the CO is remarkably increased2The charging pressure does not give the desired yield of thioquinazolinedione, only when the reaction temperature reaches above 90 ℃ is CO2The rush pressure of (A) as a secondary influence factor influences the yield of the thioquinazolinedione and increases CO2The charging pressure of (a) may increase the yield of the thioquinazolinedione to some extent.
It is a further object of the present invention to provide a 4-thioquinazolinedione derivative prepared by said method.
The invention can adopt the following technical scheme:
the target compound synthesized by the method is a 4-thioquinazoline diketone derivative.
The structure of the 4-thioquinazolinedione derivative
Figure BDA0002857576540000061
R is H, F, Cl, Br, CH mono-or polysubstituted at the ortho, meta or para positions of amino3、 CF3、OCH3、NO2、C1-8Alkyl radical, C1-8Alkoxy or C1-8One or more sulfonyl groups.
R is preferably F, Cl, Br, CF at the 5-position3、NO2、C1-8Alkyl radical, C1-8Alkoxy, F, Cl, Br, CF in position 63、OCH3、C2-8Alkyl radical, C2-8Alkoxy, Cl, Br, CF in position 73、 NO2、C1-8Alkyl radical, C2-8Alkoxy, F, Cl, Br, CF in position 83、NO2、C1-8Alkyl radical, C1-8An alkoxy group.
The structure of the o-aminobenzonitrile is as follows:
Figure BDA0002857576540000062
adding the raw material o-aminobenzonitrile derivative into solvent, and adding a certain amount of sulfide such as NaHS, KHS or Na into the mixed solution2S·9H2O, introducing CO more than 1 time equivalent2And reacting for 8-24 hours at 90-130 ℃, and treating the reaction liquid to obtain the product. After the reaction is completed, the product is generally obtained through concentration and purification processes. The concentration process adopts methods such as atmospheric distillation, reduced pressure distillation and the like, such as vacuum concentration by a rotary evaporator. The purification process refers to column chromatography or recrystallization separation and purification technology.
The o-aminobenzonitrile described in the present invention does not require treatment before use.
In the present invention, the molar ratio of the o-aminobenzonitrile to the inorganic sulfide may be adjusted as needed, and is preferably 1: 1-3, and more preferably 1: 2-3.
In the present invention, the inorganic sulfide is preferably NaHS, KHS and Na2S·9H2At least one of O.
In the present invention, the organic solvent is preferably at least one of methanol, DMF, NMP, and DMSO.
In the present invention, the solvent is preferably subjected to anhydrous treatment before use.
The reaction equation of the present invention is as follows:
Figure BDA0002857576540000071
under the action of NaHS, the invention utilizes o-aminobenzonitrile and CO2The reaction is carried out, and the 4-thio quinazoline diketone derivative is quickly and efficiently synthesized.
The thioquinazolinedione is stable and easy to obtain, and the synthesis method has the advantages of simple and convenient operation, mild conditions, short steps, high yield, easy purification of products and the like.
Compared with the traditional process, the invention has the following advantages:
1. involving CO2The activating agent is inorganic sulfide, and is low in price and easy to obtain.
2. The system is relatively simple and does not add any co-catalyst other than the reactants and inorganic sulphide.
3. The reaction process is directly dehydrated without adding other dehydrating agents, thereby reducing the cost and improving the economy.
4. The system has wide adaptability, is suitable for the synthesis of various fine chemicals with high added values, and has strong substrate applicability to various fine chemicals with high added values.
Detailed Description
The present invention is described in detail below with reference to examples, it should be noted that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention, and those skilled in the art can make some insubstantial modifications and adaptations of the present invention according to the present disclosure.
The reagents involved in the examples are all commonly available commercial products, and the NMR spectrometer model used is Agilent 500MHz DD 2.
Examples 1 to 8:
different inorganic sulfides are used to catalyze o-aminobenzonitrile and carbon dioxide to synthesize 4-sulfo-quinazoline diketone.
And (3) putting magnetons into a 10mL stainless steel high-pressure reaction kettle, sequentially adding 1mmol of o-aminobenzonitrile, inorganic sulfide and 2mL of solvent, and screwing down the reaction kettle. Preheating for 30 minutes, charging carbon dioxide with specified pressure into the reaction kettle, stirring and reacting for 24 hours at proper temperature, stopping reaction, and cooling. The gas in the reaction vessel was slowly vented, the reaction vessel was unscrewed, and the solution in the reaction vessel was transferred to a 50mL conical flask. Extracted with ethyl acetate and washed 3 times with saturated brine, and the organic phases were combined and dried over anhydrous magnesium sulfate for 30 minutes. The anhydrous magnesium sulfate was removed by filtration, and the residue was distilled under reduced pressure to obtain a crude product. The target product 4-thioquinazolinedione is obtained by separating with column chromatography (200-300 mesh silica gel) by using a mixed solvent of petroleum ether and ethyl acetate as an eluent.
Figure BDA0002857576540000081
The starting materials and reaction conditions for the examples are shown in Table 1.
TABLE 1 catalysis of CO by inorganic sulfides2Experimental result for synthesizing 4-thioquinazolinedione with o-aminobenzonitrile
Figure BDA0002857576540000091
Structural identification of 4-thioquinazolinedione
Figure BDA0002857576540000092
Characterization data for 4-thioquinazolinedione:
1H NMR(500MHz,DMSO-d6)δ＝12.76(s,1H),11.60(s,1H),8.29(dd,J＝8.1, 1.5Hz,1H),7.65(ddd,J＝8.6,7.3,1.6Hz,1H),7.22–7.12(m,2H).
13C NMR(126MHz,DMSO-d6)δ＝192.57,147.15,138.01,135.99,131.39,123.00, 119.00,114.26.
MS(ESI):m/z calcd for C8H7N2OS[M+H]+:179.02,found 179.2
the analysis result shows that the obtained target product has a correct structure.
In the examples 9 to 18, the following examples were carried out,
a10 mL stainless steel autoclave was charged with magnetons, and 1mmol of an o-aminobenzonitrile derivative, 2mmol of NaHS, and 2mL of DMF were sequentially added thereto, and the autoclave was screwed down. Filling carbon dioxide with the pressure of 4MPa into the reaction kettle, wherein the o-aminobenzonitrile and CO are generated2Is about 1: 20, stirring and reacting for 24 hours at the temperature of 100-130 ℃, stopping the reaction and cooling. The reactor was slowly vented, the reactor was unscrewed, and the solution in the reactor was transferred to a 50mL Erlenmeyer flask. Extracted with ethyl acetate and washed 3 times with saturated brine, and the organic phases were combined and dried over anhydrous magnesium sulfate for 30 minutes. The anhydrous magnesium sulfate was removed by filtration, and the residue was distilled under reduced pressure to obtain a crude product. The mixed solvent of petroleum ether and ethyl acetate is used as an eluting agent, the mixture is loaded on a column by a dry method, a solution containing the product is obtained by column chromatography (200-mesh and 300-mesh silica gel), and the solvent is removed by reduced pressure distillation. The synthesis of 4-thioxoquinazolinedione derivatives is shown in Table 2.
TABLE 2
Figure BDA0002857576540000101
Figure BDA0002857576540000111
The results of the product analyses of examples 9-18 are as follows:
EXAMPLE 9 Synthesis of 6, 7-dimethoxy-2-oxo-4-thioquinazolinedione from 2-amino-4, 5-dimethoxybenzonitrile
(1) Synthesis of 6, 7-dimethoxy-2-oxo-4-thioquinazolinedione
The crude product is separated by column chromatography (200-mesh 300-mesh silica gel), petroleum ether and ethyl acetate are used as eluent (V/V is 1: 1), and then 235.2mg of yellow solid 6, 7-dimethoxy-2-oxo-4-sulfur quinazoline diketone is obtained after separation, and the separation yield of the column chromatography is 99%.
Structural identification of 6, 7-dimethoxy-2-oxo-4-thioquinazolinedione
Figure BDA0002857576540000112
Characterization data for 6, 7-dimethoxy-2-oxo-4-thioquinazolinedione:
1H NMR(500MHz,DMSO-d6)δ＝12.50(s,1H),11.46(s,1H),7.69(s,1H),6.64(s, 1H),3.84(s,3H),3.79(s,3H).
13C NMR(126MHz,DMSO-d6)δ＝188.97,156.06,147.50,144.71,134.94,113.90, 110.09,97.30,56.05,55.63.
MS(ESI):m/z calcd for C10H11N2O3S[M+H]+:239.04,found 239.2
the analysis result shows that the target product obtained in example 9 has a correct structure.
Example 10 Synthesis of 6-fluoro-2-oxo-4-thioquinazolinedione Using 2-amino-5-fluorobenzonitrile as the starting Material.
(1) Synthesis of 6-fluoro-2-oxo-4-thioquinazolinedione
And (3) separating the crude product by column chromatography (200-mesh 300-mesh silica gel), performing gradient elution, using petroleum ether and ethyl acetate as eluent (V/V is 1: 2-1: 1), and separating to obtain 184mg of yellow solid 6-fluoro-2-oxo-4-thioquinazolinedione, wherein the separation yield of the column chromatography is 94%.
(2) Structure identification of 6-fluoro-2-oxo-4-thioquinazolinedione
Figure BDA0002857576540000121
Characterization data for 6-fluoro-2-oxo-4-thioquinazolinedione:1H NMR(500MHz,DMSO-d6)δ＝12.91(s,1H),11.67(s,1H),7.96(dd,J＝9.7, 3.0Hz,1H),7.58(td,J＝8.5,3.0Hz,1H),7.20(dd,J＝9.0,4.6Hz,1H).
13C NMR(126MHz,DMSO-d6)δ＝192.87,159.25,156.70,148.23,135.72,124.14, 118.30,114.67.
MS(ESI):m/z calcd for C8H6FN2OS[M+H]+:197.01,found196.9
the analysis result shows that the target product obtained in example 10 has a correct structure.
Example 11 Synthesis of 6-bromo-2-oxo-4-thioquinazolinedione starting from 2-amino-5-bromoxynil.
(1) Synthesis of 6-bromo-2-oxo-4-thioquinazolinedione
Separating the crude product by column chromatography (200-mesh silica gel 300 meshes), eluting with petroleum ether and ethyl acetate (V/V is 3: 1) to obtain 217mg of white solid 6-bromo-2-oxo-4-thioquinazolinedione, wherein the separation yield of column chromatography is 85%
(2) Structural identification of 6-bromo-2-oxo-4-thioquinazolinedione
Figure BDA0002857576540000122
Characterization data for 6-bromo-2-oxo-4-thioquinazolinedione:
1H NMR(500MHz,DMSO-d6)δ＝12.94(s,1H),11.75(s,1H),8.37(dd,J＝2.4, 1.0Hz,1H),7.83(ddd,J＝8.6,2.4,1.0Hz,1H),7.13(dd,J＝8.7,1.1Hz,1H).
13C NMR(126MHz,DMSO-d6)δ＝189.50,147.08,138.29,137.44,132.05,121.64, 118.36,114.79.
MS(ESI):m/z calcd for C8H6BrN2OS[M+H]+:257.9,found 257.1。
the analysis result shows that the target product obtained in example 11 has a correct structure.
Example 12 Synthesis of 7-fluoro-2-oxo-4-thioxoquinazolinedione Using 2-amino-4-fluorobenzonitrile as the starting Material.
(1) Synthesis of 7-fluoro-2-oxo-4-thioquinazolinedione
And (3) separating the crude product by column chromatography (200-mesh 300-mesh silica gel), using petroleum ether and ethyl acetate as eluent (V/V is 2: 1), and obtaining 162mg of 7-fluoro-2-oxo-4-thioquinazolinedione as a yellow solid after separation, wherein the separation yield of the column chromatography is 83%.
(2) Structural identification of 7-fluoro-2-oxo-4-thioquinazolinedione
Figure BDA0002857576540000131
Characterization data for 7-fluoro-2-oxo-4-thioquinazolinedione:
1H NMR(500MHz,DMSO-d6)δ＝11.20(s,1H),11.02(s,1H),7.76(d,J＝8.4Hz, 1H),7.04(dd,J＝8.3,1.8Hz,1H),6.98(d,J＝1.8Hz,1H).
13C NMR(126MHz,DMSO-d6)δ＝192.47,147.25,137.86,133.97,132.77,122.55, 119.08,113.25.
MS(ESI):m/z calcd for C8H6FN2OS[M+H]+: 197.01found 197.3。
the analysis result shows that the target product obtained in example 12 has a correct structure.
Example 13 Synthesis of 7-trifluoromethyl-2-oxo-4-thioquinazolinedione from 2-amino-4-trifluoromethylbenzonitrile.
(1) Synthesis of 7-trifluoromethyl-2-oxo-4-thioquinazolinedione
And (3) separating the crude product by column chromatography (200-mesh 300-mesh silica gel), using petroleum ether and ethyl acetate as eluent (V/V is 2: 1), and separating to obtain 219mg of 7-trifluoromethyl-2-oxo-4-thioquinazolinedione as a yellow solid, wherein the separation yield of the column chromatography is 89%.
(2) Structural identification of 7-trifluoromethyl-2-oxo-4-thioquinazolinedione
Figure BDA0002857576540000141
Characterization data for 7-trifluoromethyl-2-oxo-4-thioquinazolinedione:
1H NMR(500MHz,DMSO-d6)δ＝13.05(s,1H),11.81(s,1H),8.47(d,J＝8.5Hz, 1H),7.53–7.47(m,1H),7.45(d,J＝1.7Hz,1H).
13C NMR(126MHz,DMSO-d6)δ＝191.66,149.23,138.83,134.14,132.40,122.71, 119.16,113.84.
MS(ESI):m/z calcd for C9H6F3N2OS[M+H]+:247.01,found 247.3。
the analysis result shows that the target product obtained in example 13 has a correct structure.
Example 14 Synthesis of 7-chloro-2-oxo-4-thioquinazolinedione starting from 2-amino-4-chlorobenzonitrile.
(1) Synthesis of 7-chloro-2-oxo-4-thioquinazolinedione
And (3) separating the crude product by column chromatography (200-mesh silica gel 300 meshes), using petroleum ether and ethyl acetate as eluent (V/V is 2: 1), and obtaining 138mg of 7-chloro-2-oxo-4-thioquinazolinedione as a yellow solid after separation, wherein the separation yield of the column chromatography is 65%.
(2) Structural identification of 7-chloro-2-oxo-4-thioquinazolinedione
Figure BDA0002857576540000142
Characterization data for 7-chloro-2-oxo-4-thioquinazolinedione:
1H NMR(500MHz,DMSO-d6)δ＝12.77(s,1H),11.61(s,1H),8.27(p,J＝7.7Hz, 1H),7.34(dd,J＝8.6,1.1Hz,1H),7.29(d,J＝1.9Hz,1H).
13C NMR(126MHz,DMSO-d6)δ＝191.14,171.30,147.49,144.14,139.21,131.83, 120.80,112.02.
MS(ESI):m/z calcd for C8H6ClN2OS[M+H]+:212.65,found 212.3。
the analysis result shows that the target product obtained in example 14 has a correct structure.
Example 15 Synthesis of 7-methyl-2-oxo-4-thioquinazolinedione from 2-amino-4-methylbenzonitrile.
(1) Synthesis of 7-methyl-2-oxo-4-thioquinazolinedione
And (3) separating the crude product by column chromatography (200-mesh 300-mesh silica gel), using petroleum ether and ethyl acetate as eluent (V/V is 2: 1), and obtaining 172mg of 7-methyl-2-oxo-4-sulfur quinazoline diketone as a yellow solid after separation, wherein the separation yield of the column chromatography is 89%.
(2) Structural identification of 7-trifluoromethyl-2-oxo-4-thioquinazolinedione
Figure BDA0002857576540000151
Characterization data for 7-methyl-2-oxo-4-thioquinazolinedione:
1H NMR(500MHz,DMSO-d6)δ＝12.66(s,1H),11.56(s,1H),8.19(d,J＝8.3Hz, 1H),7.03(d,J＝8.4Hz,1H),6.94(s,1H),2.35(s,3H).
13C NMR(126MHz,DMSO-d6))δ＝188.97,148.23,146.65,137.75,131.11,125.24, 119.85,114.69.
MS(ESI):m/z calcd for C9H9N2OS[M+H]+:193.04,found193.2。
the analysis result shows that the target product obtained in example 15 has a correct structure.
Example 16 Synthesis of 6-nitro-2-oxo-4-thioquinazolinedione Using 2-amino-5-nitrobenzonitrile as starting Material.
(1) Synthesis of 6-nitro-2-oxo-4-thioquinazolinedione
And (3) separating the crude product by column chromatography (200-mesh 300-mesh silica gel), using petroleum ether and ethyl acetate as eluent (V/V is 1: 1), and obtaining 80mg of brown solid 6-nitro-2-oxo-4-thioquinazolinedione after separation, wherein the separation yield of the column chromatography is 36%.
(2) Structural identification of 6-nitro-2-oxo-4-thioquinazolinedione
Figure BDA0002857576540000152
Characterization data for 6-nitro-2-oxo-4-thioquinazolinedione:
1H NMR(500MHz,DMSO-d6)δ＝12.52(s,1H),11.28(s,1H),7.49(s,1H),7.01(d, J＝8.8Hz,1H),6.93(d,J＝8.7Hz,1H).
13C NMR(126MHz,DMSO-d6)δ＝191.34,147.52,144.64,128.97,123.67,120.08, 116.42,111.67.
MS(ESI):m/z calcd for C8H6N3O3S[M+H]+:223.01,found 223.4
the analysis result shows that the target product obtained in example 16 has a correct structure.
Example 17 Synthesis of 5-fluoro-2-oxo-4-thioxoquinazolinedione Using 2-amino-6-fluorobenzonitrile as the starting Material.
(1) Synthesis of 5-fluoro-2-oxo-4-thioquinazolinedione
And (3) separating the crude product by column chromatography (200-mesh silica gel 300 meshes), using petroleum ether and ethyl acetate as eluent (V/V is 2: 1), and separating to obtain 133mg of 5-fluoro-2-oxo-4-thioquinazolinedione as a yellow solid, wherein the separation yield of the column chromatography is 68%.
(2) Structure identification of 5-fluoro-2-oxo-4-thioquinazolinedione
Figure BDA0002857576540000161
Characterization data for 5-fluoro-4-thioxo-3, 4-dihydroquinazolinedione:
1H NMR(500MHz,DMSO-d6)δ＝11.86(s,1H),11.21(s,1H),7.37(t,J＝8.1Hz, 1H),6.70(d,J＝8.4Hz,1H),6.52(d,J＝7.8Hz,1H).
13C NMR(126MHz,DMSO-d6)δ＝188.45,154.09,147.09,141.34,134.23,112.65, 110.65,104.61.
MS(ESI):m/z calcd for C8H6FN2OS[M+H]+:197.01,found 197.2
the analysis result shows that the target product obtained in example 17 has a correct structure.
Example 18 Synthesis of 6-trifluoromethyl-2-oxo-4-thioquinazolinedione from 2-amino-5-trifluoromethylbenzonitrile.
(1) Synthesis of 6-trifluoromethyl-2-oxo-4-thioquinazolinedione
And (3) separating the crude product by column chromatography (200-mesh 300-mesh silica gel), using petroleum ether and ethyl acetate as eluent (V/V is 2: 1), and obtaining 240mg of yellow solid 6-trifluoromethyl-2-oxo-4-sulfur quinazoline diketone after separation, wherein the separation yield of the column chromatography is 97%.
(2) Structural identification of 6-trifluoromethyl-2-oxo-4-thioquinazolinedione
Figure BDA0002857576540000171
Characterization data for 6-trifluoromethyl-2-oxo-4-thioquinazolinedione:
1H NMR(500MHz,DMSO-d6)δ＝13.06(s,1H),11.97(d,J＝3.8Hz,1H),8.57– 8.53(m,1H),8.01–7.94(m,1H),7.34(dd,J＝8.6,3.8Hz,1H).
13C NMR(126MHz,DMSO-d6)δ＝190.90,162.47,147.31,141.69,132.45,127.71, 123.41,119.99,118.13.
MS(ESI):m/z calcd for C9H6F3N2OS[M+H]+:247.01,found 247.3。
the analysis result shows that the target product obtained in example 18 has a correct structure.
Having described embodiments of the present invention, the foregoing description is intended to be exemplary, not exhaustive, and not limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments.

Claims (5)

1. A method for preparing a 4-thioquinazolinedione derivative, which comprises the following steps:
mixing o-aminobenzonitrile, inorganic sulfide and organic solvent, charging CO2Reacting to obtain the 4-sulfo-quinazoline diketone derivative;
the structural formula of the 4-thioquinazolinedione derivative is as follows:
Figure FDA0003604529330000011
charging CO2Then, CO in the reaction kettle2The pressure of (A) is 3-6 MPa;
the reaction temperature is 90-130 ℃; the reaction time is 8-24 h;
the structure of the o-aminobenzonitrile is as follows:
Figure FDA0003604529330000012
r is H, F, Cl, Br, CF mono-or polysubstituted at the ortho, meta or para positions of amino3、NO2、C1-8Alkyl radical, C1-8Alkoxy or C1-8One or more sulfonyl groups;
the inorganic sulfide is NaSH and Na2S·9H2O, KHS, or a combination thereof.
2. The method of claim 1, wherein:
the organic solvent is at least one of methanol, dimethyl sulfoxide, N-methyl pyrrolidone and N, N-dimethylformamide.
3. The method of claim 1, wherein:
the molar ratio of the o-aminobenzonitrile to the inorganic sulfide is 1: 1-3;
the molar ratio of o-aminobenzonitrile to carbon dioxide is 1: 10 to 30 parts.
4. The method of claim 1, wherein:
the molar ratio of the o-aminobenzonitrile to the inorganic sulfide is 1: 2 to 3.
5. The method of claim 1, wherein:
the reaction temperature is 100-120 ℃, and the reaction time is 16-24 h.
CN202011553047.2A 2020-12-24 2020-12-24 4-thio quinazoline diketone derivative and preparation method thereof Active CN112624984B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202011553047.2A CN112624984B (en) 2020-12-24 2020-12-24 4-thio quinazoline diketone derivative and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202011553047.2A CN112624984B (en) 2020-12-24 2020-12-24 4-thio quinazoline diketone derivative and preparation method thereof

Publications (2)

Publication Number Publication Date
CN112624984A CN112624984A (en) 2021-04-09
CN112624984B true CN112624984B (en) 2022-06-10

Family

ID=75324405

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202011553047.2A Active CN112624984B (en) 2020-12-24 2020-12-24 4-thio quinazoline diketone derivative and preparation method thereof

Country Status (1)

Country Link
CN (1) CN112624984B (en)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109206348A (en) * 2018-09-13 2019-01-15 内蒙古工业大学 It is a kind of to utilize CO2Regulation replaces the method for cyanophenyl synthesis thiobenzamide analog derivative
CN110229109B (en) * 2019-05-28 2020-10-16 台州学院 Preparation method of 4-methylene quinazoline (sulfur) ketone compound

Also Published As

Publication number Publication date
CN112624984A (en) 2021-04-09

Similar Documents

Publication Publication Date Title
CN108440445B (en) Method for synthesizing benzothiazolones and 1, 3-disubstituted urea derivatives by CO2 activation
CN106925349A (en) A kind of solid supported type metal porphyrin catalyst and its application in terms of maleic acid is prepared
Ji et al. One-pot synthesis of 2-amino-4 (3 H)-quinazolinones via ring-opening of isatoic anhydride and palladium-catalyzed oxidative isocyanide-insertion
Sheng et al. Alcohol amine-catalyzed CO 2 conversion for the synthesis of quinazoline-2, 4-(1 H, 3 H)-dione in water
CN112624984B (en) 4-thio quinazoline diketone derivative and preparation method thereof
CN107056681B (en) A kind of support method replaces the preparation method of cloth intermediate
CN116789538B (en) Method for preparing 1, 1-dichloro pinacolone compound
CN112442008A (en) Method for preparing 1, 4-dithiine and thiophene compounds by regulating elemental sulfur and active internal alkyne at temperature and conversion reaction of compound
CN100391955C (en) Synthetic method for strotium renelate intermediate
CN110818619B (en) Synthetic method of N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide
CN111808030B (en) Method for photocatalytic synthesis of 3, 4-dihydropyrimidinone/thioketone heterocyclic compound by tantalum nitride
CN111454222B (en) Synthesis method of 2,4- (1H, 3H) -quinazolinedione and derivatives thereof
CN114478243A (en) Method for synthesizing dihydroxy dimethyl terephthalate by oxygen catalytic oxidation method
CN108299466B (en) Improved dolutegravir synthesis method
CN108191737B (en) Process for producing N- (2-methylthiophenyl) isoindole-1, 3-dione compound
CN114920733B (en) Method for synthesizing chiral isoxazole ring and carbocyclic nucleoside analogue by cycloaddition
CN117886718B (en) Preparation method of high-selectivity asymmetric urea compound and asymmetric urea compound
CN112657543B (en) Application of catalyst in synthesizing diethyl carbonate by alcoholysis of ethyl carbamate and ethanol and preparation process thereof
CN111533694B (en) Synthetic method of 2-imido hydantoin compound
CN110804007B (en) Polysubstituted pyrrole derivative and preparation method thereof
CN112390701B (en) Preparation method and application of dienestrol precursor
CN108299236B (en) Synthetic method of alpha-cyanoacrylate compound
CN108586331B (en) Intermediate for synthesizing nitrogen-containing heterocyclic compound and preparation method thereof
CN115850275A (en) Method for synthesizing zolpidem by utilizing photocatalytic three-component reaction
CN118146139A (en) Synthesis method of 4-amino-1-methylpiperidine

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
GR01 Patent grant
GR01 Patent grant