KR101580821B1 - Development of a New Synthetic Method for Quinazolinones via Aerobic Oxidation in dimethylsulfoxide - Google Patents

Abstract

The present invention relates to a method for preparing a quinazolinone derivative by using an aerobic oxidation method using an oxygen source as an oxidizing agent in a dimethylsulfoxide (DMSO) solvent in which a metal and a base are excluded, and a method for producing a quinazolinone derivative Does not require a metal catalyst such as palladium or iridium and thus has no toxicity problem due to the remaining metal and does not require a complicated process such as strong acid or base conditions, It is economical and simple to introduce a quinazolinone derivative by reacting an anthranylamide derivative with an aldehyde source.

Description

[0001] The present invention relates to a process for preparing a quinazolinone derivative by an aerobic oxidation method in a dimethylsulfoxide solvent,

The present invention relates to a method for preparing a quinazolinone derivative using an aerobic oxidation method using an oxygen source as an oxidizing agent in a dimethylsulfoxide (DMSO) solvent in which a metal and a base are excluded.

Quinazolinones and quinazolinone derivatives are one of the natural precursors present in nature and widely used as a major precursor throughout the entire chemical and medical chemistry in material science. Due to this importance, much research has been conducted on the development of a process for preparing quinazolinone derivatives. Conventional methods for preparing quinazolinone derivatives include forming amide bonds between anthranilamide derivatives and carboxylic acid derivatives, followed by dehydration using strong acids to form quinazolinones. However, the above method has a disadvantage that the reaction should be carried out at a high temperature with a strong acid. Alternatively, quinazolinone can be synthesized by forming an imine between anthranilamide and aldehyde, and then causing an oxidative cyclization reaction using a strong oxidizing agent. However, since the oxidative cyclization reaction requires a strong oxidizing agent, many by-products are formed after the reaction. Therefore, it takes a long time and a long time to separate desired compounds from the reaction solution, and the yield is not good.

In order to solve the above problems, aerobic oxidation using oxygen for direct reaction has been attracting attention in the field of organic chemistry. Fu group discloses a method for producing a quinazolinone by reacting 2-halobenzamide with an amine compound using an aerobic oxidation method in the presence of a copper-halide catalyst and a base [Organic Letters 2011, 13, No. 6, 1274- 1277], Hikawa et al. Reported that quinazolinone was prepared by reacting anthranilamide with aldehyde using an aerobic oxidation method in the presence of a palladium catalyst and TPPMS (sodium (diphenylphosphino) benzene-3-sulfonate) and water. Org. Chem. 2012 77 7046-7051]. On the other hand, Zuou group synthesizes quinazolinone precursors using iridium catalysts, and then synthesizes quinazolinones. However, in the case of most of the aerobic oxidation methods developed so far, oxygen is used as oxydane, but since the selectivity of the substrate is limited and a catalytic amount of a transition metal or a base equivalent to the equivalent or more is required, And problems of occurrence of side reactions still remain.

A problem to be solved by the present invention is to provide a method for preparing a quinazolinone derivative using an aerobic oxidation method in the presence of a metal and a base-free dimethylsulfoxide (DMSO).

In order to achieve the above-mentioned object, the present invention provides a process for producing a compound represented by the following formula (1) by reacting a compound represented by the following formula (2) and an aldehyde source in a dimethylsulfoxide solvent at 80-200 캜 Which process comprises the steps of:

[Chemical Formula 1]

(2)

Wherein the aldehyde source is any one or more selected from aldehydes represented by the following Chemical Formula 3 and 3,4-dihydropyran.

[Chemical Formula 3] [3,4-dihydropyran]

In the above Chemical Formulas 1 to 3,

R ₁ , R ₂ and R ₃ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, an alkyl group containing a carbon chain in the form of a straight, branched or cyclic chain selected from the group consisting of C 1 -C 10, phenyl, phenylpropenyl, C 7 -C 14 C7-C14 alkoxyphenyl, nitrophenyl, methoxycarbonylphenyl, ethoxycarbonylphenyl, aminophenyl, cyanophenyl, halophenyl, dihalophenyl, trihalophenyl, perhalophenyl, naphthyl, An anthracenyl group, and a C4-C12 heteroaryl group.

Wherein said alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, isohexyl, cyclohexyl, normal heptyl, isoheptyl and cycloheptyl,

Wherein the alkylphenyl group is selected from the group consisting of methylphenyl, ethylphenyl, propylphenyl, dimethylphenyl, diethylphenyl and methylethylphenyl,

Wherein said alkoxyphenyl group is selected from the group consisting of methoxyphenyl and ethoxyphenyl,

Wherein said heteroaryl group is selected from the group consisting of furanyl, methylfuranyl, ethylfuranyl, dimethylfuranyl, diethylfuranyl, thiophenyl, methylthiophenyl, ethylthiophenyl, dimethylthiophenyl, But are not limited to, at least one member selected from the group consisting of a fluorine atom,

According to an embodiment of the present invention, the reaction may be performed using at least one oxygen source selected from oxygen and air as an oxidizing agent. The oxygen source is not particularly limited as long as it can supply oxygen molecules during the reaction And may be any one or more selected from ozone, oxygen plasma, hydrogen peroxide, and a solvent in which oxygen is dissolved.

According to another embodiment of the present invention, the reaction can be carried out by reacting for 1-60 hours.

The reaction can produce water as a by-product.

The process for preparing the quinazolinone derivative according to the present invention can produce quinazolinone in an environmentally friendly manner by using only an oxygen source in the presence of dimethylsulfoxide as an oxidizing agent. The process for preparing a quinazolinone derivative according to the present invention does not require a metal catalyst such as palladium or iridium and thus has no toxicity problem due to the remaining metal, and can be used in a severe acid or base condition, a low temperature reaction, It is economical and simple that an anthranilamide derivative and an aldehyde source are reacted to introduce a quinazolinone derivative.

1 is a ¹ H-nuclear magnetic resonance spectrum of Example 1-3 of the present invention (a: Example 1, b: Example 2, c: Example 3).
2 is a ¹ H-nuclear magnetic resonance spectrum of Example 4-6 of the present invention (a: Example 4, b: Example 5, c: Example 6).
3 is a ¹ H-nuclear magnetic resonance spectrum of Example 7-9 of the present invention (a: Example 7, b: Example 8, c: Example 9).
4 is a ¹ H-nuclear magnetic resonance spectrum of Example 10-12 of the present invention (a: Example 10, b: Example 11, c: Example 12).
5 is a ¹ H-nuclear magnetic resonance spectrum of Example 13-15 of the present invention (a: Example 13, b: Example 14, c: Example 15).
6 is a ¹ H-nuclear magnetic resonance spectrum of Example 16-18 of the present invention (a: Example 16, b: Example 17, c: Example 18).
FIG. 7 is a ¹ H-nuclear magnetic resonance spectrum of Example 22-24 of the present invention (a: Example 22, b: Example 23, c: Example 24).
8 is a ¹ H-nuclear magnetic resonance spectrum of Example 26-28 of the present invention (a: Example 26, b: Example 27, c: Example 28).
9 is a ¹ H-nuclear magnetic resonance spectrum of Example 30-32 of the present invention (a: Example 30, b: Example 31, c: Example 32).
10 is a ¹ H-nuclear magnetic resonance spectrum of Examples 33, 34 and 37 of the present invention (a: Example 33, b: Example 34, c: Example 37).
11 is a ¹ H-nuclear magnetic resonance spectrum of Example 38 of the present invention (a: 2- (4-hydroxybutyl) quinazolin-4 (3H) -one, b: 8,9-dihydro -6H-pyrido [2,1-b] quinazolin-11 (7H) -one.

Hereinafter, the present invention will be described in more detail.

The present invention relates to a process for producing a quinazolinone derivative, which comprises reacting a compound represented by the following formula (2) and an aldehyde source in a dimethylsulfoxide solvent at 80-200 캜 to produce a compound represented by the following formula The method provides:

[Chemical Formula 1]

(2)

In the above Chemical Formula 1 or Chemical Formula 2,

R ₁ , R ₂ and R ₃ are the same or different and each independently represents an alkyl group containing a carbon chain of hydrogen, halogen, a C 1 -C 10 linear, branched or cyclic group, a phenyl group, a phenylpropenyl group, C14 alkylphenyl, C7-C14 alkoxyphenyl, nitrophenyl, methoxycarbonylphenyl, ethoxycarbonylphenyl, aminophenyl, cyanophenyl, halophenyl, dihalophenyl, trihalophenyl, perhalophenyl, A naphthyl group, an anthracenyl group, and a C4-C12 heteroaryl group.

Wherein said alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, isohexyl, cyclohexyl, normal heptyl, isoheptyl and cycloheptyl,

Wherein the alkylphenyl group is selected from the group consisting of methylphenyl, ethylphenyl, propylphenyl, dimethylphenyl, diethylphenyl and methylethylphenyl,

Wherein said alkoxyphenyl group is selected from the group consisting of methoxyphenyl and ethoxyphenyl,

Wherein said heteroaryl group is selected from the group consisting of furanyl, methylfuranyl, ethylfuranyl, dimethylfuranyl, diethylfuranyl, thiophenyl, methylthiophenyl, ethylthiophenyl, dimethylthiophenyl, But are not limited to, at least one member selected from the group consisting of a fluorine atom,

The reaction is characterized by an aerobic oxidation carried out using at least one oxygen source selected from oxygen and air as an oxidizing agent. The oxygen source is not particularly limited as long as it can supply oxygen molecules during the reaction, An oxygen source may be provided by stirring using an open flask system in which the inlet is opened without closing the reaction vessel so that the reaction vessel may be exposed to the atmosphere, or any one or one selected from ozone, oxygen plasma, hydrogen peroxide, Or more may be used. However, when oxygen is used as an oxidizing agent, a quinazolinone derivative can be obtained in a high yield in a short time. It is preferable that the open flask system is economical and safe in industrial use.

According to the present invention, the aldehyde source means a compound capable of being converted to an aldehyde and an aldehyde upon the reaction. The aldehyde source according to the present invention is selected from an aldehyde represented by the following Chemical Formula 3 and 3,4-dihydropyran It can be any one or more:

[Chemical Formula 3] [3,4-dihydropyran]

In the above formula 3,

R ₁ represents a hydrogen atom, a halogen atom, an alkyl group containing a linear, branched or cyclic C1-C10 carbon chain, a phenyl group, a phenylpropenyl group, an alkylphenyl group of C7-C14, an alkoxyphenyl group of C7- The heterocyclic group is selected from the group consisting of an alkyl group, an alkoxy group, an alkoxy group, an alkoxy group, an alkoxy group, an alkoxycarbonyl group, an alkoxycarbonyl group, an alkoxycarbonylphenyl group, an ethoxycarbonylphenyl group, an aminophenyl group, a cyanophenyl group, a halophenyl group, dihalophenyl, trihalophenyl, perhalophenyl, However,

Wherein said alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, isohexyl, cyclohexyl, normal heptyl, isoheptyl and cycloheptyl,

Wherein the alkylphenyl group is selected from the group consisting of methylphenyl, ethylphenyl, propylphenyl, dimethylphenyl, diethylphenyl and methylethylphenyl,

Wherein said alkoxyphenyl group is selected from the group consisting of methoxyphenyl and ethoxyphenyl,

Wherein said heteroaryl group is selected from the group consisting of furanyl, methylfuranyl, ethylfuranyl, dimethylfuranyl, diethylfuranyl, thiophenyl, methylthiophenyl, ethylthiophenyl, dimethylthiophenyl, But are not limited to, at least one member selected from the group consisting of a fluorine atom,

When 3,4-dihydropyran is used as the aldehyde source, the 3,4-dihydropyran is used in order to prepare the quinazolinone according to the present invention. Anthranilamide derivatives; Oxygen source; And dimethylsulfoxide at 80 to 200 ° C for 1 to 60 hours, preferably at a temperature of 100 ° C or more, the reaction rate is fast and quinazolinone is produced at a high yield have. If the reaction temperature is lower than the above range, aerobic oxidation hardly occurs and quinazolinone is not produced or the amount of quinazolinone produced is insignificant. When the reaction temperature is in the above range, the reaction rate and yield are improved It is not desirable because it is not economical because it is not present or small.

The base used when 3,4-dihydropyrane is used as the aldehyde source is not limited as long as it can convert 3,4-dihydropyran to aldehyde. Specifically, p-toluenesulfonic acid (p -toluenesulfonic acid, TsOH).

According to the present invention, dimethylsulfoxide is used as a solvent because the reaction yield is high and a quinazolinone oxidative cyclization reaction is performed in a short time without using a metal catalyst or a base, Do not. For example, when dimethylformamide is used as a solvent, the reaction proceeds, but the reaction time is long, the yield is low, and immigration by-products are generated, which is not preferable.

According to the present invention, the reaction can be carried out using dimethylsulfoxide as a solvent, but even when another organic solvent is added to dimethylsulfoxide, a quinazolinone oxidative cyclization reaction can be performed. However, in the latter case, the time for synthesizing quinazolinone may be longer than in the case of using only dimethylsulfoxide. However, in order to introduce a substituent into the resulting quinazolinone, a substituent is added to the resulting quinazolinone to effect a one-pot reaction And can be preferably used.

For example, as shown in Reaction Scheme 1 below, when an anthranilamide derivative and an aldehyde are reacted using an aerobic oxidation method by adding only dimethylsulfoxide as a solvent according to the present invention, the reaction time is short, Jollyonone is produced and is stable.

When a reaction vessel containing an anthranilamide derivative and an aldehyde according to the present invention is added with another organic solvent to dimethylsulfoxide as a solvent and reacted using an aerobic oxidation method, the reaction time may be longer than that of dimethylsulfoxide, It can be economically and economically stable. The process for preparing quinazolinone according to the present invention does not require a separate purification process because water is produced as a by-product, and a quinazolinone into which the substituent is introduced can be prepared by further adding a substituent to the reaction vessel have.

[Reaction Scheme 1]

According to the present invention, the organic solvent used together with dimethyl sulfoxide (DMSO) may include dimethylformamide (DMF), tetrahydrofuran, dioxane, acetonitrile, water, methylene chloride, chloroform, But the present invention is not limited thereto.

In the case where only dimethylsulfoxide is used as a solvent, the reaction may proceed even with the use of a catalyst or a base. However, when the catalyst or the base is used, the synthesis yield is lowered. More desirable.

In addition, according to the present invention, it is preferable that the process for producing the quinazolinone further comprises water, but quinazolinone is not produced in an environment in which moisture is excluded, and an imine intermediate may be produced.

According to the present invention, when the open source flask system is used to supply the oxygen source, moisture can be supplied from the water vapor contained in the air, so that the reaction can be performed without adding water through a separate process.

The reaction produces water as a by-product.

The compound represented by the formula (1) according to the present invention may be specifically at least one compound selected from the following formulas (4) to (38).

[Chemical Formula 4] < EMI ID =

[Chemical Formula 8] < EMI ID =

[Chemical Formula 11] [Chemical Formula 12]

[Chemical Formula 14] [Chemical Formula 15]

[Chemical Formula 18] [Chemical Formula 18]

[Chemical Formula 20]

[Chemical Formula 22]

[Chemical Formula 25]

[Chemical Formula 30]

[Chemical Formula 32] [Chemical Formula 33]

[Chemical Formula 35] [Chemical Formula 35]

[Chemical Formula 37]

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

Example

In the following examples, unless otherwise stated, all reactions were carried out in an atmosphere in which the reactants were exposed to air, and the progress of the reaction was checked using a thin film chromatography method. The compounds prepared in the examples according to the present invention were analyzed using a Varian Gemini 300 (300 MHz), a Varian Gemini 400 (400 MHz) or a Bruker 600 (600 MHz) Nuclear magnetic resonance (NMR) spectra were measured.

Example  1. 2- Phenylquinazoline -4 (3H) - one Manufacturing

1.0 mmol of anthranilamide and 1.2 mmol of benzaldehyde were placed in a reaction vessel and dissolved in 5 mL of dimethylsulfoxide. The reaction mixture was stirred at 100 째 C in an open flask system, and the reaction was progressed by thin layer chromatography. When the anthranylamide was exhausted, the reaction was terminated, and after cooling to room temperature, 100 mL of water was added to form a precipitate, which was then filtered to obtain a precipitate. The precipitate was recrystallized in ethanol to obtain the desired compound. Further, in order to further obtain the objective compound remaining in the crystal filtrate, the desired compound was obtained by silica gel column chromatography using a solvent of hexane: ethyl acetate = 3: 1 to 1: 1. Reaction time 12 hours.

A white solid. Yield: 0.200 g (90%). ^{1 H NMR (400 MHz, DMSO} -d 6, ppm) δ 8.18 (d, J = 7.43 Hz, 3H), 7.88 (t, J = 7.43 Hz, 1H), 7.78 (d, J = 8.22 Hz, 1H) , 7.55-7.65 (m, 4H).

Example  2. 2- (4- Methoxyphenyl ) quinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 1 except that 4-methoxybenzaldehyde was used instead of benzaldehyde. Reaction time 12 hours.

A white solid. Yield: 0.212 g (84%). H NMR (400 MHz, DMSO- d 6, ppm) δ 12.37 (s, 1H), 8.16 (d, J = 8.61 Hz, 2H), 8.10 (d, J = 7.83 Hz, 1H), 7.78 (dd, J = 7.83, 7.04 Hz, 1H) , 7.67 (d, J = 8.22 Hz, 1H), 7.45 (dd, J = 7.43, 7.04 Hz, 1H), 7.04 (d, J = 9.00 Hz, 2H), 3.82 (s , 3H).

Example  3.2- (4- Methylphenyl ) quinazoline -4 (3H) - one's  Produce

Methylbenzaldehyde was used in place of benzaldehyde, the target compound was obtained. Reaction time 12 hours.

white solid. Yield: 0.210 g (89%). ^{1 H NMR (400 MHz, DMSO} -d 6, ppm) δ 2.43 (s, 1H), 8.13 (d, J = 7.83 Hz, 1H), 8.07 (d, J = 7.43 Hz, 2H), 7.81 (t, J = 7.43 Hz, 1H), 7.71 (d, J = 7.83 Hz, 1H), 7.49 (t, J = 7.43 Hz, 1H), 7.34 (d, J = 7.83 Hz, 2H), 2.37 (s, 3H) .

Example  4. 2- (4- Chlorophenyl ) quinazoline -4 (3H) - one's  Produce

The objective compound was obtained by the method of Example 1 except that 4-chlorobenzaldehyde was used instead of benzaldehyde. Reaction time 18 hours.

A white solid. Yield: 0.226 g (88%). ^{1 H NMR (400 MHz, DMSO} -d 6, ppm) δ 12.60 (s, 1H), 8.13-8.18 (m, 3H), 7.82 (dd, J = 7.43, 7.04 Hz, 1H), 7.71 (d, J = 8.22 Hz, 1 H), 7.60 (d, J = 8.61 Hz, 2H), 7.50 (dd, J = 7.43, 7.04 Hz, 1H).

Example  5. 2- (4- Methoxycarbonylphenyl ) quinazoline -4 (3H) - one's  Produce

The objective compound was obtained by the method of Example 1 except that 4-methoxycarbonylbenzaldehyde was used instead of benzaldehyde. Reaction time 12 hours.

A white solid. Yield: 0.276 g (98%). ^{1 H NMR (400 MHz, DMSO} -d 6, ppm) δ 12.69 (s, 1H), 8.27 (d, J = 8.22 Hz, 2H), 8.14 (d, J = 7.83 Hz, 1H), 8.07 (d, J = 8.22 Hz, 2H), 7.83 (dd, J = 7.43, 7.04 Hz, 1H), 7.74 (d, J = 8.22 Hz, 1H), 7.53 (dd, J = 7.43, 7.04 Hz, 1H), 3.87 ( s, 3H). ^{13 C NMR (150 MHz, DMSO} -d 6, ppm) δ 166.21, 162.50, 152.02, 149.00, 137.49, 134.94, 132.53, 129.64, 128.57, 128.01, 127.32, 126.35, 121.77, 52.66. _{HRMS (EI) calcd for C 16} H 12 N 2 O 3 (M) +.

Example  6. 2- (4- Cyanophenyl ) quinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 1 except that 4-cyanobenzaldehyde was used instead of benzaldehyde. Reaction time 30 hours.

A white solid. Yield: 0.235 g (95%). ^{1 H NMR (400 MHz, DMSO} -d 6, ppm) δ 12.74 (s, 1H), 7.32 (d, J = 7.04 Hz, 2H), 8.16 (d, J = 7.83 Hz, 1H), 8.03 (d, J = 6.65 Hz, 2H), 7.86 (t, J = 7.43 Hz, 1H), 7.77 (d, J = 8.22 Hz, 1H), 7.56 (dd, J = 7.43, 7.04 Hz, 1H).

Example  7. 2- ( Perfluorophenyl ) quinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 1 except that perfluorobenzaldehyde was used instead of benzaldehyde. Reaction time 30 hours.

A white solid. Yield: 0.238 g (76%). ^{1 H NMR (400 MHz, DMSO} -d 6, ppm) δ 13.05 (s, 1H), 8.21 (d, J = 7.83 Hz, 1H), 7.91 (dd, J = 7.83, 7.43 Hz, 1H), 7.77 ( d, J = 8.22 Hz, 1H), 7.66 (t, J = 7.43 Hz, 1H).

Example  8. 2- (2- Methylphenyl ) quinazoline -4 (3H) - one's  Produce

2-methylbenzaldehyde was used in place of benzaldehyde, to obtain the target compound. Reaction time 17 hours.

A white solid. Yield: 0.201 g (85%). ^{1 H NMR (400 MHz, DMSO} -d 6, ppm) δ 12.47 (s, 1H), 8.18 (d, J = 7.83 Hz, 1H), 7.85 (dd, J = 7.43, 7.04 Hz, 1H), 7.70 ( (d, J = 8.22 Hz, 1H), 7.51-7.57 (m, 2H), 7.45 (dd, J = 7.43, 7.04 Hz, 1H), 7.32-7.37 (m, 2H), 2.40 (s,

Example  9. 2- (2- Chlorophenyl ) quinazoline -4 (3H) - one's  Produce

2-chlorobenzaldehyde was used in place of benzaldehyde, to obtain the desired compound. Reaction time 17 hours.

A white solid. Yield: 0.221 g (86%). ^{1 H NMR (400 MHz, DMSO} -d 6, ppm) δ 12.67 (s, 1H), 8.19 (d, J = 7.83 Hz, 1H), 7.87 (dd, J = 7.83, 7.43 Hz, 1H), 7.64- 7.74 (m, 4 H) 7.59 (dd, J = 7.43, 7.04 Hz, 2H), 7.51 (dd, J = 7.43, 7.04 Hz, 1H).

Example  10. 2- ( Naphthalen -One- yl ) quinazoline -4 (3H) - one's  Produce

The target compound was obtained by the method of Example 1 except that 1-naphthaldehyde was used instead of benzaldehyde. Reaction time 36 hours.

A light yellow solid. Yield: 0.216 g (79%). ^{1 H NMR (400 MHz, DMSO} -d 6, ppm) δ 12.65 (s, 1H), 8.21 (d, J = 7.83 Hz, 1H), 8.15 (d, J = 7.83 Hz, 1H), 8.11 (d, J = 8.22 Hz, 1H), 8.04 (d, J = 8.22 Hz, 1H), 7.86 (dd, J = 7.83, 7.43 Hz, 1H), 7.77 (d, J = 7.04 Hz, 1H), 7.72 (d, J = 7.83 Hz, 1H), 7.55 7.65 (m, 4H).

Example  11. 2- (2- Naphthalen -One- yl ) quinazoline -4 (3H) - one's  Produce

The desired compound was obtained by the method of Example 1 except that 2-naphthaldehyde was used instead of benzaldehyde. Reaction time 18 hours.

A light yellow solid. Yield: 0.224 g (82%). ^{1 H NMR (400 MHz, DMSO} -d 6, ppm) δ 12.65 (s, 1H), 8.79 (s, 1H), 8.27 (d, J = 8.61 Hz, 1H), 8.15 (d, J = 7.83 Hz, 1H), 7.98-8.06 (m, 3H ), 7.84 (t, J = 7.43 Hz, 1H), 7.77 (d, J = 8.22 Hz, 1H), 7.58-7.64 (m, 2H), 7.51 (t, J = 7.43 Hz, 1 H).

Example  12. 2- ( Furan -2- yl ) quinazoline -4 (3H) - one's  Produce

2-carbaldehyde was used in place of benzaldehyde, the desired compound was obtained. Reaction time 18 hours.

A white solid. Yield: 0.201 g (95%). ¹ H NMR _{(400 MHz, DMSO-d 6} , ppm) δ 12.49 (s, 1H), 8.09 (d, J = 7.83 Hz, 1H), 7.97 (s, 1H), 7.78 (t, J = 7.43 Hz, 1H), 7.66 (d, J = 8.22 Hz , 1H), 7.60 (s, 1H), 7.46 (dd, J = 7.43, 7.04 Hz, 1H), 6.72 (s, 1H).

Example  13. 2- ( Thiophen -2- yl ) quinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 1 except that thiophene-2-carbaldehyde was used instead of benzaldehyde. Reaction time 36 hours.

A white solid. Yield: 0.213 g (93%). ^{1 H NMR (400 MHz, DMSO} -d 6, ppm) δ 12.64 (s, 1H), 8.20 (d, J = 3.13 Hz, 1H), 8.09 (d, J = 7.04 Hz 1H), 7.84 (d, J = 4.70 Hz, 1H), 7.78 (t, J = 7.04 Hz , 7.62 (d, J = 7.83 Hz, 1H), 7.46 (t, J = 7.43 Hz, 1H), 7.21 (t, J = 3.91 Hz, 1H).

Example  14. 2- ( Pyridine -2- yl ) quinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 1 except that picoline aldehyde was used instead of benzaldehyde. Reaction time 36 hours.

A white solid. Yield: 0.214 g (96%). ^{1 H NMR (400 MHz, DMSO} -d 6, ppm) δ 11.84 (s, 1H), 8.73 (d, J = 3.13 Hz, 1H), 8.43 (d, J = 7.83 Hz 1H), 8.16 (d, J = 7.83 Hz, 1H), 8.05 (t, J = 7.43 Hz , 1H), 7.85 (t, J = 7.43 Hz, 1H), 7.78 (d, J = 7.83 Hz, 1H), 7.64 (dd, J = 5.87, 5.43 Hz, 1H), 7.55 (t, J = 7.43 Hz , 1H).

Example  15. (E) -2- ( Styryl ) quinazoline -4 (3H) - one Manufacturing

(E) -3- (pyridin-2-yl) acrylaldehyde was used in place of benzaldehyde, the objective compound was obtained. Reaction time 12 hours.

A yellow solid. Yield: 0.177 g (71%). ^{1 H NMR (400 MHz, DMSO} -d 6, ppm) δ 12.37 (s, 1H), 8.13 (d, J = 7.43 Hz, 1H), 7.98 (d, J = 16.43 Hz, 1H), 7.82 (t, J = 7.04 Hz, 1H), 7.69 (dd, J = 7.43, 6.65 Hz, 2H), 7.51-4.73 (m, 4H), 7.03 (d, J = 16.04 Hz, 1H).

Example  16. 2- ( tert - Butyl ) quinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 1 except that pivalic aldehyde was used instead of benzaldehyde. Reaction time 36 hours.

A white solid. Yield: 0.085 g (42%). ^{1 H NMR (400 MHz, DMSO} -d 6, ppm) δ 11.86 (s, 1H), 8.07 (d, J = 7.83 Hz, 1H), 7.76 (dd, J = 8.22, 7.04 Hz 1H), 7.60 (d , J = 7.83 Hz, 1H), 7.46 (t, J = 7.43 Hz, 1H), 1.33 (s, 9H).

Example  17. 2- Cyclohexylquinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 1 except that cyclohexanecarbaldehyde was used instead of benzaldehyde. Reaction time 18 hours.

A white solid. Yield: 0.221 g (97%). ^{1 H NMR (400 MHz, DMSO} -d 6, ppm) δ 12.07 (s, 1H), 8.03 (d, J = 7.43 Hz, 1H), 7.73 (t, J = 7.04 Hz 1H), 7.56 (d, J = 8.22 Hz, 1H), 7.41 (dd, J = 7.43, 2H), 1.65 (m, 2H), 1.65 (m, 2H), 1.65 (m, 2H).

Example  18. 2- Hexylquinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 1 except that heptanal was used instead of benzaldehyde. Reaction time 36 hours.

A white solid. Yield: 0.211 g (92%). ^{1 H NMR (400 MHz, DMSO} -d 6, ppm) δ J = 7.83 Hz, 1H), 7.77 (t, J = 7.04 Hz 1H), 7.60 (d, J = 8.22 Hz, 1H), 7.46 (dd, J = 7.04 Hz, 1 H), 2.60 (m, 2H), 1.72 (m, 2H), 1.29 (m, 6H), 0.86 (m, 3H).

Example  19. Quinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 1 except that formaldehyde was used instead of benzaldehyde. Reaction time 12 hours.

A white solid. Yield: 0.098 g (67%). ^{1 H NMR (400 MHz, DMSO} -d 6, ppm) δ 12.37 (s, 1H), 8.13 (d, J = 7.43 Hz, 1H), 7.98 (d, J = 16.43 Hz, 1H), 7.82 (t, J = 7.04 Hz, 1H), 7.69 (dd, J = 7.43, 6.65 Hz, 2H), 7.51-4.73 (m, 4H), 7.03 (d, J = 16.04 Hz, 1H).

Example  20. 2- (4- nitrophenyl ) quinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 1 except that 4-nitrobenzaldehyde was used instead of benzaldehyde. Reaction time 12 hours.

white solid. Yield: 95%

Example  21. 2- (2- nitrophenyl ) quinazoline -4 (3H) - one Manufacturing

2-nitrobenzaldehyde was used in place of benzaldehyde to obtain the target compound. Reaction time 15 hours.

white solid. Yield: 97%.

Example  22. 2,3- Diphenylquinazoline -4 (3H) - one Manufacturing

1.0 mmol of N-phenyl-anthranilamide and 1.2 mmol of benzaldehyde were placed in a reaction vessel and dissolved in 5 mL of dimethylsulfoxide. The reaction mixture was stirred at 120 ° C. in an open flask system. Respectively. When the anthranylamide was exhausted, the reaction was terminated, cooled to room temperature and extracted with water and methylene chloride. The organic layer was separated, water was removed with a desiccant (magnesium sulfate), and the concentrate was concentrated. The concentrate was separated by silica gel column chromatography using a solvent of hexane: ethyl acetate = 5: 1 to obtain the desired compound. Reaction time 48 hours.

A white solid. Yield: 0.240 g (80%). ^{1 H NMR (400 MHz, CDCl} 3, ppm) δ 8.37 (d, J = 7.97 Hz, 1H), 7.83 (m, 2H), 7.58-7.52 (m, 1H), 7.33-7.15 (m, 10H).

Example  23. 2- (4- Methoxyphenyl ) -3- phenylquinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 22 except that 4-methoxybenzaldehyde was used instead of benzaldehyde. Reaction time 48 hours.

A white solid. Yield: 0.254 g (77%). ^{1 H NMR (400 MHz, CDCl} 3, ppm) δ 8.34 (d, J = 7.83 Hz, 1H), 7.81-7.80 (m, 2H), 7.52 (m, 2H), 7.36-7.26 (m, 4H), 7.16 (d, J = 7.04 Hz, 2H), 6.72 (d, J = 8.61 Hz, 2H), 3.75 (s, 3H).

Example  24. 2- (4- Methyphenyl ) -3- phenylquinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 22 except that 4-methylbenzaldehyde was used instead of benzaldehyde. Reaction time 48 hours.

A white solid. Yield: 0.226 g (72%). ^{1 H NMR (400 MHz, CDCl} 3, ppm) δ 8.34 (d, J = 7.97 Hz, 1H), 7.82 (m, 2H), 7.55-7.50 (m, 1H), 7.33-7.28 (m, 3H), 7.24-7.21 (m, 2H), 7.17-7.15 (m, 2H), 7.02-6.99 (m, 2H), 2.26 (s, 3H).

Example  25. 2- (4- Chlorophenyl ) -3- phenylquinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 22 except that 4-chlorobenzaldehyde was used instead of benzaldehyde. Reaction time 48 hours.

A white solid. Yield: 0.240 g (72%).

Example  26. 2- (4- Methoxycarbonylphenyl ) -3- phenylquinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 22 except that 4-methoxycarbonylbenzaldehyde was used instead of benzaldehyde. Reaction time 48 hours.

A white solid. Yield: 0.301 g (84%). ^{1 H NMR (400 MHz, CDCl} 3, ppm) δ 8.35 (d, J = 7.83 Hz, 1H), 7.87 (d, J = 8.22 Hz, 2H), 7.82-7.81 (m, 2H), 7.57-7.53 ( m, 1H), 7.41 (d , J = 8.22 Hz, 2H), 7.32-7.26 (m, 3H), 7.13 (d, J = 7.04 Hz, 2H), 3.87 (s, 3H).

Example  27. 2- (2- Methyphenyl ) -3- phenylquinazoline -4 (3H) - one Manufacturing

Methylbenzaldehyde was used in place of benzaldehyde, the desired compound was obtained. Reaction time 48 hours.

A white solid. Yield: 0.225 g (72%). ^{1 H NMR (400 MHz, CDCl} 3, ppm) δ 8.36 (d, J = 8.22 Hz, 1H), 7.81-7.80 (m, 2H), 7.55-7.51 (m, 1H), 7.27-7.18 (m, 3H ), 7.12-6.99 (m, 6H), 2.28 (s, 3H).

Example  28. 2- (2- Chlorophenyl ) -3- phenylquinazoline -4 (3H) - one Manufacturing

The target compound was obtained by the method of Example 22 except that 2-chlorobenzaldehyde was used instead of benzaldehyde. Reaction time 48 hours.

A white solid. Yield: 0.226 g (68%). ¹ H NMR (400 MHz, CDCl ₃ , ppm)? 8.37 (d, J = 7.83 Hz, 1H), 7.83-7.82 (m, 2H), 7.58-7.54 (m, 1H), 7.40-7.26 ), 7.22-7.08 (m, 5H).

Example  29. 2- ( Furan -2- yl ) -3- phenylquinazoline -4 (3H) - one Manufacturing

2-carbaldehyde was used in place of benzaldehyde, the objective compound was obtained. Reaction time 48 hours.

A light yellow solid. Yield: 0.187 g (65%).

Example  30. 3- Phenyl -2-( thiophen -2- yl ) quinazoline -4 (3H) - one Manufacturing

The desired compound was obtained by the method of Example 22 except that thiophene-2-carbaldehyde was used instead of benzaldehyde. Reaction time 48 hours.

A light yellow solid. Yield: 0.222 g (73%). ¹ H NMR (400 MHz, CDCl ₃ , ppm)? 8.26 (d, J = 7.83 Hz, 1 H), 7.75-7.74 (m, 2H), 7.51-7.44 (m, 4H), 7.33-7.32 ), 6.75-6.74 (m, 1 H), 6.33 - 6.32 (m, 1 H).

Example  31. 3- phenylquinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 22 except that formaldehyde was used instead of benzaldehyde.

A white solid. Yield: 0.084 g (38%). ^{1 H NMR (400 MHz, CDCl} 3, ppm) δ 8.38 (d, J = 8.22 Hz, 1H), 8.15 (s, 1H), 7.83-7.77 (m, 2H), 7.58-7.43 (m, 6H).

Example  32. 2- Hexyl -3- phenylquinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 22 except that heptanal was used instead of benzaldehyde. Reaction time 48 hours.

A white solid. Yield: 0.129 g (42%). ¹ H NMR (400 MHz, CDCl ₃ , ppm)? 8.27 (d, J = 7.83 Hz, 1H), 7.79-7.70 (m, 2H), 7.58-7.44 (m, 4H), 7.27-7.25 ), 2.42 (t, J = 7.83 Hz, 2H), 1.67 (m, 3H), 1.23-1.18 (m, 5H), 0.83 (dd, J = 7.04,6.65 Hz, 3H).

Example  33. 3- benzyl -2- phenylquinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 22 except that N-benzyl-anthranylamide was used instead of N-phenyl-anthranylamide. Reaction time 48 hours.

A white solid. Yield: 0.269 g (86%). ^{1 H NMR (400 MHz, CDCl} 3, ppm) δ8.38 (d, J = 8.22 Hz, 1H), 7.80-7.75 (m, 2H), 7.54-7.52 (m, 1H), 7.48-7.44 (m, 1H), 7.41-7.33 (m, 4H), 7.21-7.19 (m, 3H), 6.94-6.92 (m, 2H), 5.27 (s, 2H).

Example  34. 3- methyl -2- phenylquinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 22 except that N-methyl-anthranylamide was used instead of N-phenyl-anthranylamide. Reaction time 48 hours.

A white solid. Yield: 0.188 g (80%). ^{1 H NMR (400 MHz, DMSO} , ppm) δ 8.19 (d, J = 8.22 Hz, 1H), 7.84 (dd, J = 7.83, 7.43 Hz, 1H), 7.69-7.67 (m, 3H), 7.59-7.55 (m, 4 H), 3.36 (s, 3 H).

Example  35. 3- methylquinazoline -4 (3H) - one Manufacturing

The objective compound was obtained by the method of Example 22 except that N-methyl-anthranylamide was used instead of N-phenyl-anthranylamide. Reaction time 48 hours.

A white solid. Yield: 42%.

Example  36. 2- (4- hydroxybutyl ) quinazoline -4 (3H) - one Manufacturing

1.0 mmol of anthranilamide, 1.2 mmol of 3,4-dihydro-2H-pyran and 10 mol% of p-toluenesulfonic acid (TsOH) were dissolved in 5 mL of dimethylsulfoxide, And the reaction progress was confirmed by thin film chromatography method in the middle. After 24 hours, the reaction mixture was extracted with water and diethyl ether. The organic layer was collected, and water was removed with a desiccant (magnesium sulfate), followed by concentration. The concentrate was separated by silica gel column chromatography to obtain the desired compound.

A white solid. Yield: 0.112 g (51%). ^{1 H NMR (400 MHz, DMSO} , ppm) δ 12.18 (s, br, 1H), 8.08 (d, J = 7.83 Hz, 1H), 7.77 (dd, J = 8.22, 6.65 Hz, 1H), 7.59 (d , J = 7.83 Hz, 1H) , 7.46 (t, J = 7.43 Hz, 1H), 4.42 (s, br, 1H), 3.42 (dd, J = 6.65, 6.26 Hz, 2H), 2.60 (dd, J = 7.83, 7.43 Hz, 2H), 1.75 (m, 2H), 1.47 (m, 2H).

Example  37. N, 2- diphenylquinazoline -4- amine ( one - pot reaction  One)

1.0 mmol of anthranylamide, 1.2 mmol of benzaldehyde and 3.0 mmol of dimethylsulfoxide were placed in a reaction vessel and dissolved in 5 mL of dimethylformamide, followed by stirring at 100 ° C in an open flask system. Respectively. After 48 hours, the anthranilamide was exhausted to complete the reaction. After cooling to room temperature, 2.0 mmol of phosphoryl chloride (POCl ₃ ) was added and further stirred at 50 ° C. After the quinazolinone was exhausted, 1.1 mmol of aniline was added and the mixture was further stirred at 50 DEG C, and the reaction progress was confirmed by thin film chromatography in the middle. After completion of the reaction, the reaction mixture was extracted with water and diethyl ether, and the organic layer was collected, and water was removed with a desiccant (magnesium sulfate), followed by concentration. The concentrate was separated by silica gel column chromatography using a solvent of hexane: ethyl acetate = 7: 1 to obtain the desired compound.

A white solid. Yield: 0.111 g (37%). ^{1 H NMR (400 MHz, DMSO} , ppm) δ 9.90 (s, 1H), 8.61-8.59 (d, J = 7.83 Hz, 1H), 8.50-8.46 (m, 2H), 8.01-7.99 (d, J = 7.83 Hz, 2H), 7.89-7.76 (m, 2H), 7.63-7.47 (m, 6H), 7.19 (t, J = 7.04 Hz, 1H).

Example  38. 8,9- dihydro -6H- pyrido [2,1-b] quinazolin-11 (7H) - one ( one - pot reaction  2)

1.0 mmol of anthranilamide, 1.2 mmol of 3,4-dihydro-2H-pyran and 10 mol% of p-toluenesulfonic acid (TsOH) were dissolved in 5 mL of dimethylsulfoxide, And the reaction progress was confirmed by thin film chromatography method in the middle. After the reaction was completed, the mixture was cooled to room temperature, and then 1.1 mmol of di-propyl azodicarboxylate and 1.3 mmol of triphenylphosphine were added and ryks were further added. After the reaction was completed, the reaction mixture was extracted with water and diethyl ether, and then the organic layer was collected, and water was removed with a desiccant (magnesium sulfate), followed by concentration. The concentrate was separated by silica gel column chromatography using a solvent of hexane: ethyl acetate = 5: 1 to obtain the desired compound.

A white solid. Yield: 0.113 g (56%). ^{1 H NMR (400 MHz, DMSO} , ppm) δ 8.09 (d, J = 7.83 Hz, 1H), 7.77 (t, J = 7.43 Hz, 1H), 7.56 (d, J = 7.83 Hz, 1H), 7.45 ( (d, J = 7.43, 7.04 Hz, 1H), 3.94 (t, J = 5.87 Hz, 2H), 2.90 (t, J = 6.26 Hz, 2H), 1.91-1.82 (m, 4H).

Test Example  One.

In order to confirm the synthesis yield according to the reaction environment, anthranilamide and benzaldehyde were reacted at various organic solvents and temperatures, as shown in Reaction Scheme 2 and Tables 1 and 2 below.

[Reaction Scheme 2]

Test Example  1.1. Solvent change

The reaction temperature was fixed at 100 占 폚 and thunazolinone was synthesized according to the above Reaction Scheme 2. As shown in the following Table 1, when dimethylsulfoxide was used as a solvent, all the reactions proceeded within 12 hours (reaction condition 1.1). On the other hand, when molecular sieves (molecular sieves) having a pore size of 4 Å were added to dimethyl sulfoxide, the quinazolinone did not react and partly formed an imine intermediate. As a result, it was confirmed that moisture affects the reaction. On the other hand, when the solvent was used as dimethylformamide, the rate of the reaction was slow and the ratio of the imine intermediate was high. When the solvent was used as water, most of it formed an imine intermediate, and no quinazolinone was produced. From the above results, it was confirmed that the process for preparing quinazolinone according to the present invention is carried out in a dimethylsulfoxide solvent not containing water (or containing water).

division menstruum Reaction time (h) yield(%)
1a: 3a: 4a Other Reaction conditions 1.1 DMSO 12 68: 32: 0 4 ÅMS addition Reaction conditions 1.2 DMSO 12 0: 0: 100 - Reaction conditions 1.3 DMF 12 18:38:44 - Reaction conditions 1.4 1,4-dioxane 12 21:55:24 - Reaction conditions 1.5 H ₂ O 12 0: 100: 0 - Reaction conditions 1.6 toluene 12 36: 64: 0 -

In Table 1,

DMSO is dimethyl sulfoxide,

DMF is dimethylformamide,

4 ÅMS is molecular seives with a pore size of 4 Å.

Test Example  1.2. Temperature change

The reaction solvent was fixed with dimethylsulfoxide and quinazolinone was synthesized according to the above-mentioned Reaction Scheme 2. As shown in Table 2, the reaction did not proceed even in the 24-hour reaction at the temperature of the non-heated laboratory (reaction condition 2.1). When the reaction temperature was 60 ° C and 80 ° C, the quinazolinone . On the other hand, the starting material was completely consumed in 12 hours at 100 ° C, and the resulting compound was identified as quinazolinone. When the reaction was carried out at 120 ° C, the reaction was completed within 3.5 hours. From the above results, it was confirmed that the process for preparing quinazolinone according to the present invention is preferably carried out at a temperature of 100 ° C or higher.

division Temperature (℃) Reaction time (h) yield(%) Reaction conditions 2.1 room Temp. 24 No reaction Reaction conditions 2.2 60 24 Trace detection Reaction conditions 2.3 80 24 Trace detection Reaction conditions 2.4 100 12 > 99 Reaction conditions 2.5 120 3.5 > 99

Test Example  2.

In order to prove that the process of preparing the quinazolinone according to the present invention is an oxidation reaction by an oxygen source, the reaction was carried out under an argon atmosphere in which oxygen was excluded. However, the reaction did not proceed under an argon atmosphere.

Test Example  3.

In order to confirm the effect of the nucleophiles on the preparation of the quinazolinones according to the present invention, various nucleophiles were added to the imine intermediate to carry out the reaction, and these are shown in the following Scheme 3 and Table 3.

[Reaction Scheme 3]

In the above Reaction Scheme 3,

Nu is a nucleophile.

division Nucleophile Reaction time (h) yield(%) Other Reaction conditions 3.1 NaCN 24 57 - Reaction conditions 3.2 KI 24 45 - Reaction conditions 3.3 NaI 24 66 - Reaction conditions 3.4 NaOPh 24 56 - Reaction conditions 3.5 NaOAc 24 58 - Reaction conditions 3.6 - 18 94 - Reaction conditions 3.7 - 24 <5 Ar airflow

As shown in Table 3, it was confirmed that the quinazolinone was produced in the most excellent yield under the reaction condition 3.6 in which nothing was added, and the yield was lowered in the presence of the nucleophile.

Claims (7)

A compound represented by the following formula (1) is prepared by reacting a compound represented by the following formula (2) and the following formula (3) or 3,4-dihydropyrane in a dimethylsulfoxide solvent at 80-200 캜 &Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt;
[Chemical Formula 1]

(2)

[Chemical Formula 3] [3,4-dihydropyran]

In the above Chemical Formulas 1 to 3,
R ₁ , R ₂ and R ₃ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, an alkyl group containing a carbon chain in the form of a straight, branched or cyclic chain selected from the group consisting of C 1 -C 10, phenyl, phenylpropenyl, C 7 -C 14 C7-C14 alkoxyphenyl, nitrophenyl, methoxycarbonylphenyl, ethoxycarbonylphenyl, aminophenyl, cyanophenyl, halophenyl, dihalophenyl, trihalophenyl, perhalophenyl, naphthyl, Anthracenyl group, and a C4-C12 heteroaryl group. The method according to claim 1,
Wherein the reaction is carried out using at least one oxygen source selected from oxygen and air as an oxidizing agent. delete The method according to claim 1,
Wherein the reaction is carried out by reacting for 1 to 60 hours. The method according to claim 1,
Wherein said alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, isohexyl, cyclohexyl, normal heptyl, isoheptyl and cycloheptyl,
Wherein the alkylphenyl group is selected from the group consisting of methylphenyl, ethylphenyl, propylphenyl, dimethylphenyl, diethylphenyl and methylethylphenyl,
Wherein said alkoxyphenyl group is selected from the group consisting of methoxyphenyl and ethoxyphenyl,
Wherein said heteroaryl group is selected from the group consisting of furanyl, methylfuranyl, ethylfuranyl, dimethylfuranyl, diethylfuranyl, thiophenyl, methylthiophenyl, ethylthiophenyl, dimethylthiophenyl, A thiophene group, a thiophene group, a thiophene group, a thienylthio group, a thienylthio group, a thienylthio group, a thienylthio group, a thienylthio group, The method according to claim 1,
Wherein said reaction is to produce water as a by-product. The method according to claim 1,
Wherein the reaction further comprises water. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt;

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