KR101304693B1 - Enviornmentally synthetic method for 2,3-dihydroquinazolinone derivatives and their spirooxindole derivatives - Google Patents

Abstract

The present invention relates to an environmentally friendly method for synthesizing 2,3-dihydroquinazolinone derivatives and their spirooxindole derivatives. anhydride) to synthesize 2,3-dihydroquinazolinone derivatives, and also to react various amines and some isatins with isatoic anhydride in the presence of ethylenediaminediacetate catalyst in water solvent. It is possible to synthesize a biologically interesting spirooxindole derivative having a dihydroquinazolinone skeleton, and the synthesis method enables a simple and environmentally friendly compound at high yield, and is useful for large scale synthesis. .

Description

Environment-friendly synthesis of 2,3-dihydroquinazolinone derivatives and their spirooxindole derivatives {2.3-dihydroquinazolinone derivatives and their spirooxindole derivatives}

The present invention relates to a new method for the simple and eco-friendly synthesis of 2,3-dihydroquinazolinone derivatives and spirooxindole derivatives having 2,3-dihydroquinazolinone rings exhibiting various physiological activities.

2,3-dihydroquinazolinone derivatives possess a wide range of biological, pharmaceutical and medical properties including the activity of anticancer, antibiotic, antipyretic, analgesic, antihypertonic, diuretic, antihistamine, antidepressant and vasodilation. It is an important fused heterocyclic compound shown. In addition, 2,3-dihydroquinazolinones have been reported to act as potent tubulin inhibitors with large antiproliferative activity in several types of human cancer cells. Furthermore, these compounds can act similarly to colchicine, a substance that blocks cell division. Many methods of synthesizing 2,3-dihydroquinazolinone derivatives from isatoic anhydride (path a) and 2-aminobenzaldehyde (path b) are known (Scheme 1). ). That is, the method through path a is [bmin] BF ₄ , p-TsOH, silica sulfuric acid, Al (H ₂ P) ₄ ) ₃ , KAl (SO ₄ ) ₂ · 12H ₂ O (alum), montmorillonite K-10 The condensation reaction of isatoic anhydride, primary amine and aromatic aldehyde compound was used under the catalyst of zinc, perfluorooctanoate, gallium triflate and Amberlyst-15 / microwave. Path b methods include condensation of 2-aminobenzamide systems with aldehydes in the presence of p- TsOH / DDQ, I ₂ , FeCl ₃ , CuCl ₂ , TiCl ₄ / Zn, chiral phosphoric acid and ionic liquid / water.

[Reaction Scheme 1]

Spirooxindole derivatives also show a variety of biological efficacy and have been of interest to the synthesis of spirooxindole derivatives because of their unique structure and very important pharmaceutical activity. Recently, two synthetic methods have been developed for spirooxindole compounds having dihydroquinazolinone rings through multicomponent reactions (Scheme 2). In other words, the known content is a method of condensing isatins, amines and isatoic anhydride using a KAl (SO ₄ ) ₂ H ₂ O catalyst (c) and chiral phosphoric acid. Is a method of synthesizing spirooxindole derivatives through the reaction of isatitin and 2-aminobenzamide in the presence of (path d).

[Reaction Scheme 2]

Synthesis methods of 2,3-dihydroquinazolinone-based and spiroxoxindole derivatives have been developed and reported, but still simple, low-cost, environmentally friendly synthesis methods are still required. Recently, Bronsted acids and bases have been widely used as active catalysts for various reactions in organic synthesis. In particular, the inventors have developed a reaction for synthesizing various forms of benzopyrene rings using Bronsted acid and ethylenediaminediacetate as base catalysts.

As a result of the ongoing study using ethylenediaminediacetate as a catalyst, the inventors have used isatoic anhydride, amines, and benzaldehydes to purify water under an ethylenediaminediacetate catalyst. A method for synthesizing 2,3-dihydroquinazolin-4 (1H) -one derivatives has been developed using environmentally friendly solvents. In addition, a method for synthesizing spirooxindole containing dihydroquinazolinone rings under an ethylenediaminediacetate catalyst using isatoic anhydride, amines, and isatins .

It is an object of the present invention to provide a novel method for synthesizing a 2,3-dihydroquinazolinone derivative and a spirooxindole derivative having a 2,3-dihydroquinazolinone ring which is efficient and simple and eco-friendly. .

In order to achieve the above object, the present invention is a three-component reaction of isatoic anhydride, amines and benzaldehydes in water under an ethylenediamine diacetate (EDDA) catalyst. It provides a method for synthesizing 2,3-dihydroquinazolinone derivatives represented by the formula (1).

[Formula 1]

또는

중 어느 하나이고, X는 C1 내지 C4의 알콕시 또는 할로겐 중 어느 하나이며,In Formula 1, R ¹

or

X is any one of C1 to C4 alkoxy or halogen,

이며, Y₁은 수소, CH₃CHCH₃, C1 내지 C4의 알콕시 또는 할로겐 중 어느 하나이고, Y₂은 수소 또는 C1 내지 C4의 알킬 중 어느 하나이며, n은 0 내지 4의 정수이다.R ² is arylamine,

Y ₁ is hydrogen, CH ₃ CHCH ₃ , C 1 to C 4 alkoxy or halogen, Y ₂ is hydrogen or C 1 to C 4 alkyl, and n is an integer of 0 to 4.

,

,

,

,

,

및

으로 이루어진 군에서 선택하여 사용할 수 있다.The amines are

,

,

,

,

,

And

Can be selected from the group consisting of.

,

,

및

으로 이루어진 군에서 선택하여 사용할 수 있다.The benzaldehyde is

,

,

And

Can be selected from the group consisting of.

In addition, the present invention is represented by the formula (2) in the three-component reaction of isatoic anhydride, amines (amines) and isatins (isatins) in water under an ethylenediamine diacetate (EDDA) catalyst Provided is a method for synthesizing a spirooxindole derivative comprising a dihydroquinazolinone ring.

(2)

이며, Y₁은 수소, CH₃CHCH₃, C1 내지 C4의 알콕시 또는 할로겐 중 어느 하나이고, Y₂은 수소 또는 C1 내지 C4의 알킬 중 어느 하나이며, n은 0 내지 4의 정수이거나; C1 내지 C7의 알킬이거나;

; 또는 수소 중 어느 하나이다.In Formula 2, R ₁

Y ₁ is hydrogen, CH ₃ CHCH ₃ , C1 to C4 alkoxy or halogen, Y ₂ is hydrogen or C1 to C4 alkyl, n is an integer from 0 to 4; C1 to C7 alkyl;

; Or hydrogen.

,

,

,

,

,

,

,

,

,

,

, 및

으로 이루어진 군에서 선택하여 사용할 수 있다.The amines are

,

,

,

,

,

,

,

,

,

,

, And

Can be selected from the group consisting of.

,

, 및

으로 이루어진 군에서 선택하여 사용할 수 있다.The isatin is

,

, And

Can be selected from the group consisting of.

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

In recent years, environmentally friendly technologies have been used to make various organic compounds. Of these, the technology of using water as a solvent is the most environmentally friendly, inexpensive, environmentally friendly, non-toxic and safe to use. The present inventors first determine isatoic anhydride ( 1 ), aniline (aniline, 2a ) in several solvents including ethanol, acetonitrile, methylene chloride, toluene and water. ), And benzaldehyde ( 3a ) was investigated whether 4a can be synthesized by a three-element reaction with EDDA as a catalyst (Scheme 3). When the reaction was carried out under an ethylenediaminediacetate catalyst using water as a solvent, the expected product 4a was obtained with better reaction time and better yield (94%) compared to other organic solvents. The nonpolar solvents of methylene chloride and toluene did not produce the expected product due to the insolubility of isatoic anhydride. When ethanol was used as the solvent, 4a was obtained with a yield of 50-60%. As a solvent, water increases the reaction rate due to features including hydrophobic effect, large dielectric constant, strong hydrogen bonds, high heat capacity and optimum oxygen solubility. These results are shown in Table 1. When a lower alcohol such as ethanol was used as a solvent, a product was obtained at a low yield, and therefore, it is most preferable to use water as a solvent which is high in yield, induces a fast reaction, and is environmentally friendly and low cost.

Scheme 3

compound EDDA (mol%) menstruum Condition Yield (%) One - ethanol Reflux, 12 hours 25 2 10 ethanol Reflux, 12 hours 50 3 20 ethanol Reflux, 12 hours 55 4 40 ethanol Reflux, 12 hours 60 5 - Acetonitrile Reflux, 12 hours <5 6 20 Acetonitrile Reflux, 12 hours 20 7 40 Acetonitrile Reflux, 12 hours 30 8 20 Methylene chloride Reflux, 12 hours - 9 20 toluene Reflux, 12 hours - 10 - water Reflux, 12 hours 36 11 10 water Reflux, 12 hours 80 12 20 water Reflux, 5 hours 94

After conditioning, more reactions with various amines and benzaldehydes were investigated, and the results are listed in Table 2.

compound Amine Aldehyde Reaction time (hr) product Yield (%) One

10

86 2

7

93 3

8

91 4

7

90 5

6

92 6

6

90 7

7

89 8

8

88 9

7

87 10

6

92

Direct three-element reactions include electron-donating (entries 1-5) or electron-withdrawing groups (entries 6-7), phenethylamine (entries 8-9) and 4- It proceeds well in various arylamines with phenylbutylamine (4-phenylbutylamine, entry 10). In addition, the reaction of various benzaldehydes and arylamines, including groups that give or attract electrons to the benzene ring, also yields the expected product 4b-4h. Reaction with other primary amines with aromatic rings yields the expected product 4i-4k with yields of 88-92% (entries 8-10).

In addition, the present invention relates to a method for synthesizing a spirooxindole derivative having a dihydroquinazolinone ring, isatoic anhydride ( 1 ), aniline (aniline, 2a ), and isatin (isatin, 5a). The triurea reaction was carried out under ethylenediaminediacetate (EDDA) catalyst. Ethylenediaminediacetate (EDDA) was used as a catalyst under water solvent to reflux for 5 hours using 2a, 5a and 1 to obtain compound 6a in 94% yield (Scheme 4).

[Reaction Scheme 4]

To find out the generality of this reaction, the reaction was attempted with the addition of isatoic anhydride (1) to various amines and several isatines. The results are listed in Table 3. Reaction with aniline having both groups (entries 1-2) and (entry 3) to the benzene ring yielded the product 6b-6d in 89-96% yield. Reaction with other primary amines with aromatic rings yielded the expected 6e-6i in 82-92% yield (entries 4-8). In addition, when the aliphatic amine having a chain and a cyclic ring was applied, the expected cyclic substances 6j and 6k were obtained in 91-89% yield. Also, application of ammonium acetate yielded 6 l (93%). In addition, reaction of 5-bromoissatin (5b) with 1-methylisatin (5e) to several anilines was able to successfully produce 6m-6q of the product in 82-93% yield (entries 12-16). The reactions allowed rapid access to 6b-6q, a variety of spiroxoxindole derivatives with dihydroquinazolinone sites.

Amine Isatin product Reaction time
(h) yield
(%) One

7 92 2

6 96 3

9 89 4

7 90 5

10 82 6

10 88 7

6 92 8

7 92 9

7 91 10

7 89 11 NH ₄ OAc

6 93 12

8 93 13

10 82 14

10 90 15

8 92 16

8 88

The formation of 4a and 6a can be explained by the mechanism shown below, as shown in Scheme 5. Ethylenediaminediacetate can act as Bronsted acid. The carbonyl group of isatoic anhydride (1) can be protonated by ethylenediaminediacetate to produce intermediate 7 which facilitates the nucleophilic attack of aniline (2a) at the carbonyl site. The nucleophilic addition of decarbonic acid and aniline (2a) of compound 7 produced 8, 2-aminobenzamide. Condensation of protonated benzaldehyde and 8 produced imine 9, which produced the final product 4a by intramolecular cyclization. Similarly, condensation of protonated isatin with 8 and reaction with ethylenediaminediacetate yielded imine 10, with 10 being the intramolecular cyclization to yield the product 6a. Therefore, the synthesis method according to the present invention is to obtain the product in a very simple method as a one-pot reaction.

[Reaction Scheme 5]

The synthesis method according to the present invention can obtain a high yield of 2,3-dihydroquinazolinone derivatives and spirooxindole derivatives having a 2,3-dihydroquinazolinone ring with various physiological activities, and the synthesis is easy. In addition, there are various advantages that are not only environmentally friendly but also applicable to large scale synthesis.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited by these examples.

All experiments below were performed in aqueous solution. Isatoic anhydride, aldehydes, isatitin and amines were obtained from Aldrich Chemical. Silica gel plates (Art. 5554) coated with Merck's fluorescent markers were used for analytical TLC. ¹ H NMR and ¹³ C NMR spectra were recorded on a Bruker Model ARX (300 and 75 MHz, respectively) spectrometer in DMSO-d ₆ as solvent chemical shift. IR spectra were recorded on a Jasco FTIR 5300 spectrometer. HRMS spectra were performed by the Korean Society of Base Science.

< Example  1> Synthesis of Compound 4a

(1.0 mmol) 및

(1.0 mmol)이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 5시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:94%) Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol) and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 5 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 94%).

mp 205-206 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.77 (1H, d, J = 7.8 Hz), 7.64 (1H, s), 7.42-7.18 (11H, m), 6.79 (1H, d, J = 8.1 Hz ), 6.74 (1H, t, J = 7.2 Hz), 6.30 (1H, s);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 162.2, 146.5, 140.7, 140.6, 133.7, 128.5, 128.3, 128.2, 127.9, 126.5, 126.2, 125.9, 117.4, 115.3, 114.7, 72.6;

IR (KBr) 3427, 3294, 3061, 2832, 1633, 1511, 1392, 1332, 1257, 1158, 1025, 754 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₀ H ₁₆ N ₂ O: 300.1263. Found: 300.1265.

< Example  2> Synthesis of Compound 4b

(1.0 mmol) 및

(1.0 mmol)이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 10시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:86%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol) and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 10 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 86%).

mp 209-210 ° C;

¹ H NMR (300MHz, DMSO-d ₆ ) δ 7.75 (1H, d, J = 7.5 Hz), 7.54 (1H, s), 7.33-7.19 (5H, m), 7.14 (1H, s), 7.03 (2H , t, J = 8.7Hz), 6.88-6.85 (2H, m), 6.77 (1H, t, J = 8.1Hz), 6.22 (1H, s), 3.71 (3H, s), 2.27 (3H, s) ;

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 162.2, 159.0, 146.5, 140.8, 137.8, 133.6, 132.7, 128.3, 127.9, 127.8, 126.8, 126.6, 123.2, 117.4, 115.4, 114.7, 113.6, 72.3, 55.0, 20.8 ;

IR (KBr) 3424, 3301, 2961, 2833, 1634, 1507, 1393, 1301, 1248, 1170, 1026, 830, 766 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₂ H ₂₀ N ₂ O ₂ : 344.1525. Found: 344.1525.

< Example  3> Synthesis of Compound 4c

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:93%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 93%).

mp 190-192 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.95 (1H, d, J = 8.4 Hz), 7.74 (1H, d, J = 6.9 Hz), 7.68 (1H, d, J = 2.4 Hz), 7.59 ( 1H, d, J = 8.4Hz), 7.37-7.17 (7H, m), 6.78-6.71 (2H, m), 6.29 (1H, d, J = 2.4Hz), 2.93-2.84 (1H, m), 1.18 (6H, d, J = 6.9 Hz);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 162.05, 146.2, 139.9, 138.4, 133.7, 132.8, 130.1, 128.9, 128.3, 127.02, 126.5, 121.04, 117.6, 115.4, 114.8, 71.8, 32.9, 23.7;

IR (KBr) 3425, 3282, 2960, 1645, 1511, 1390, 1327, 1240, 990, 8826, 754 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₃ H ₂₁ ClN ₂ O: 376.1342. Found: 376.1339.

< Example  4> Synthesis of Compound 4d

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 8시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:91%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 8 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 91%).

mp 171-172 ° C;

¹ H NMR (300MHz, DMSO-d ₆ ) δ 7.75 (1H, d, J = 7.5 Hz), 7.55 (1H, s), 7.32-7.21 (7H, m), 6.86 (2H, d, J = 8.4Hz ), 6.74 (2H, t, J = 8.4 Hz), 6.19 (1H, s), 3.70 (3H, s), 2.91-2.82 (1H, m), 1.19 (6H, d, J = 6.9 Hz);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 162.1, 159.05, 146.4, 145.9, 138.6, 133.5, 132.8, 127.8, 127.6, 126.3, 125.9, 117.3, 115.4, 114.7, 113.6, 72.2, 54.9, 32.9, 23.7;

IR (KBr) 3420, 3298, 2956, 1630, 1508, 1392, 1332, 1249, 1177, 1027, 833, 700 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₄ H ₂₄ N ₂ O ₂ : 372.1838. Found: 372.1840.

< Example  5> Synthesis of Compound 4e

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:90%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and then recrystallized in ethanol to obtain pure product (yield: 90%).

mp 210-212 ° C;

¹ H NMR (300MHz, DMSO-d ₆ ) δ 7.74 (1H, d, J = 7.5 Hz), 7.58 (1H, s), 7.28-7.18 (5H, m), 6.94 (1H, s), 6.83-6.63 (4H, m), 6.18 (1H, s), 5.98 (2H, s), 2.92-2.85 (1H, m), 1.19 (6H, d, J = 6.6 Hz);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 162.1, 147.3, 147.1, 146.3, 146.0, 138.5, 134.9, 133.6, 127.9, 126.4, 125.8, 119.9, 117.4, 115.4, 114.8, 107.8, 106.6, 101.1, 72.2, 32.9 , 23.7;

IR (KBr) 3437, 2960, 1644, 1509, 1401, 1237, 1028, 755 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₄ H ₂₂ N ₂ O ₃ : 386.1630. Found: 386.1629

< Example  6> Synthesis of Compound 4f

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 6시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:92%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 6 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 92%).

mp 227-228 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.74 (1H, d, J = 7.8 Hz), 7.44 (1H, s), 7.31-7.23 (3H, m), 7.15 (2H, d, J = 8.7 Hz ), 6.89-6.84 (4H, m) 6.75 (2H, t, J = 7.8 Hz), 6.16 (1H, s), 3.73 (3H, s), 3.70 (3H, s);

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 162.3, 159.1, 157.2, 146.6, 133.5, 132.7, 127.9, 127.8, 127.4, 117.3, 115.2, 114.6, 113.7, 113.6, 72.8, 55.1, 55.0;

IR (KBr) 3426, 2936, 2837, 1636, 1510, 1394, 1441, 1243, 1174, 1025, 996, 830, 762 cm ^-1 ;

HRMS m / z (M ⁺ ) calcd for C ₂₂ H ₂₀ N ₂ O ₃ : 360.1474. Found: 360.1477.

< Example  7> Synthesis of Compound 4g

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 6시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 90%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 6 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and then recrystallized from ethanol to obtain pure product (yield: 90%).

mp 259-260 ° C;

¹ H NMR (300MHz, DMSO-d ₆ ) δ 7.74 (1H, d, J = 7.8 Hz), 7.49 (1H, s), 7.29-7.12 (7H, m), 6.86 (2H, d, J = 8.7Hz ), 6.76 (2H, t, J = 7.8 Hz), 6.23 (1H, s), 3.70 (3H, s);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 162.5, 159.2, 146.8, 133.7, 132.2, 128.8, 128.7, 128.09, 127.9, 117.4, 115.4, 115.1, 115.0, 114.6, 113.6, 72.6, 55.0;

IR (KBr) 3427, 3302, 1643, 1504, 1390, 1305, 1245, 1026, 994, 832, 760 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₁ H ₁₇ FN ₂ O ₂ : 348.1274. Found: 348.1272.

< Example  8> Synthesis of Compound 4h

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:89%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 89%).

mp 252-253 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.74 (1H, d, J = 7.5 Hz), 7.55 (1H, s), 7.31-7.26 (2H, m), 7.22-7.14 (2H, m), 6.95 (1H, s), 6.66-6.72 (5H, m), 6.21 (1H, s), 5.98 (2H, s);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 162.4, 147.3, 147.2, 136.7, 134.1, 133.7, 128.8, 128.7, 127.8, 120.5, 117.5, 115.4, 115.1, 114.9, 114.6, 107.7, 106.9, 101.1, 72.7;

IR (KBr) 3426, 1641, 1501, 1447, 1393, 1248, 1027, 996, 758 cm ^-1 ;

HRMS m / z (M ⁺ ) calcd for C ₂₁ H ₁₅ FN ₂ O ₃ : 362.1067. Found: 362.1064.

< Example  9> Synthesis of Compound 4i

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 8시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:88%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 8 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and then recrystallized from ethanol to obtain pure product (yield: 88%).

mp 183-185 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.72 (1H, d, J = 7.8 Hz), 7.35-7.17 (9H, m), 6.93 (2H, d, J = 8.7 Hz), 6.75-6.67 (2H m, 5.82 (1H, s), 4.06-3.97 (1H, m), 3.73 (3H, s), 3.05-2.87 (2H, m), 2.76-2.52 (1H, m);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 162.3, 159.4, 146.5, 139.0, 133.1 132.9, 128.6, 128.5, 128.3, 127.7, 127.4, 126.2, 117.0, 114.7, 114.2, 113.8, 70.3, 55.1, 46.0;

IR (KBr) 3426, 3299, 1629, 1509, 1408, 1299, 1249, 1173, 1025, 997, 763 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₃ H ₂₂ N ₂ O ₂ : 358.1681. Found: 358.1679.

< Example  10> Synthesis of Compound 4j

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:87%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain a pure product (yield: 87%).

mp 147-148 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.65 (1H, d, J = 7.8 Hz) 7.29-7.16 (6H, m), 6.88-6.78 (3H, m), 6.69-6.62 (3H, m), 5.98 (2H, s), 5.76 (1H, s), 4.04-3.88 (1H, m), 3.01-2.84 (2H, m), 2.77-2.67, (1H, m);

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 162.1, 147.4, 147.3, 146.3, 139.0, 134.9, 133.1, 128.5, 128.3, 127.3, 126.1, 119.7, 117.0, 114.6, 114.1, 107.9, 106.4, 101.1, 70.2 , 46.0, 33.5;

IR (KBr) 3427, 1634, 1484, 1411, 1248, 1026, 994, 756 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₃ H ₂₀ N ₂ O ₃ : 372.1474. Found: 372.1471.

< Example  11> Synthesis of Compound 4k

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 6시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:92%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 6 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 92%).

mp 129-130 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.65 (1H, d, J = 7.8 Hz), 7.39-7.11 (11H, m), 6.81-6.61 (2H, m), 5.83 (1H, d, J = 2.1 Hz), 3.41-3.35 (2H, m), 2.53 (2H, t, J = 6.9 Hz), 1.58-1.45 (4H, m);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 162.2, 145.9, 142.03, 140.2, 133.2, 132.9, 128.4, 128.26, 128.21, 127.9, 127.4, 125.6, 117.3, 115.0, 114.3, 69.4, 44.3, 34.8, 28.3, 27.1 ;

IR (KBr) 3426, 3297, 2938, 2859, 1630, 1489, 1437, 1413, 1320, 1089, 996, 826, 749 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₄ H ₂₃ ClN ₂ O: 390.1499. Found: 390.1499.

< Example  12> Synthesis of Compound 6a

(1.0 mmol) 및

(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 5시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 94%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol) and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 5 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 94%).

mp 264-266 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.39 (1H, s), 7.68 (1H, d, J = 7.5 Hz), 7.60 (1H, s), 7.53 (1H, d, J = 7.5 Hz), 7.30 (1H, t, J = 7.8 Hz), 7.24-7.12 (4H, m), 7.01-6.98 (2H, m), 6.92 (1H, t, J = 7.5 Hz), 6.78-6.70 (2H, m) , 6.64 (1H, d, J = 7.5 Hz);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 175.6, 163.8, 146.3, 141.4, 138.3, 134.2, 134.0, 129.9, 129.7, 129.2, 128.3, 127.9, 118.4, 115.0, 114.6, 114.1, 112.6, 76.8;

IR (KBr) 3447, 3303, 1721, 1644, 1615, 1486, 1358, 1194, 1105, 1012, 964, 865, 752 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₁ H ₁₅ N ₃ O ₂ : 341.1164. Found: 341.1161.

< Example  12> Synthesis of Compound 6b

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 92%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 92%).

mp 274-276 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.40 (1H, s), 7.66 (1H, d, J = 7.8 Hz), 7.59 (1H, s), 7.53 (1H, d, J = 7.2 Hz), 7.30 (1H, t, J = 7.8 Hz), 7.15 (1 H, t, J = 7.5 Hz), 7.07 (1 H, t, J = 7.2 Hz), 6.98-6.90 (3H, m), 6.82 (1 H, s ), 6.75 (1H, t, J = 8.4 Hz), 6.70 (1H, d, J = 8.1 Hz), 6.64 (1H, d, J = 7.5 Hz), 2.15 (3H, s);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 174.3, 163.9, 146.5, 143.6, 138.3, 134.1, 131.4, 128.8, 128.7, 127.9, 127.1, 126.6, 123.1, 118.2, 115.1, 114.6, 109.3, 76.6, 21.2

IR (KBr) 3298, 3206, 3093, 1724, 1643, 1616, 1485, 1361, 1236, 1193, 1100, 1048, 963, 751 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₂ H ₁₇ N ₃ O ₂ : 355.1321. Found: 355.1318.

< Example  13> Synthesis of Compound 6c

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 6시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 96%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 6 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and then recrystallized from ethanol to obtain pure product (yield: 96%).

mp 276-278 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.36 (1H, s), 7.66 (1H, d, J = 7.5 Hz), 7.56 (1H, s), 7.52 (1H, d, J = 7.5 Hz), 7.29 (1H, t, J = 8.1 Hz), 7.15 (1H, t, J = 7.5 Hz), 7.08-6.87 (5H, m), 6.77-6.63 (3H, m), 2.79-2.73 (1H, m) , 1.09 (6H, d, J = 6.9 Hz);

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 175.3, 163.6, 147.4, 146.0, 141.5, 135.6, 133.5, 130.6, 129.0, 127.5, 127.4, 126.3, 126.2, 122.1, 117.6, 114.5, 114.0, 110.0, 76.3 , 32.7, 23.6, 23.5;

IR (KBr) 3311, 3066, 2961, 1725, 1632, 1511, 1484, 1359, 1214, 1190, 1105, 1051, 955, 817, 752 cm ^-1

HRMS m / z (M ⁺ ) calcd for C ₂₄ H ₂₁ N ₃ O ₂ : 383.1634. Found: 383.1630.

< Example  14> Synthesis of Compound 6d

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 9시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 89%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 9 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 89%).

mp 295-296 ° C;

¹ H NMR (300MHz, DMSO-d ₆ ) δ 10.47 (1H, s), 7.67 (2H, t, J = 3.3 Hz), 7.59 (1H, d, J = 10.5 Hz), 7.31 (1H, t, J = 7.2 Hz), 7.18 (1H, t, J = 7.5 Hz), 7.09-6.92 (5H, m), 6.78-6.65 (3H, m);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 175.4, 163.9, 146.3, 141.4, 134.4, 134.3, 134.1, 129.8, 129.7, 127.9, 118.4, 116.2, 115.9, 114.8, 114.6, 114.2, 112.6, 76.9

IR (KBr) 3272, 3066, 1726, 1642, 1616, 1509, 1483, 1360, 1328, 1221, 1197, 1154, 1099, 961, 827, 750 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₁ H ₁₄ FN ₃ O ₂ : 359.1070. Found: 359.1068.

< Example  15> Synthesis of Compound 6e

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 90%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and then recrystallized from ethanol to obtain pure product (yield: 90%).

mp 210-211 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.34 (1H, s), 7.72 (1H, d, J = 7.8 Hz), 7.45 (1H, s), 7.36-7.24 (3H, m), 7.17-7.15 (3H, m), 6.93-6.88 (3H, m), 6.83 (1H, d, J = 7.8 Hz), 6.76 (1H, t, J = 7.5 Hz), 6.67 (1H, d, J = 7.5 Hz) , 4.48 (1H, d, J = 15.3 Hz), 4.15 (1H, d, J = 15.3 Hz);

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 175.4, 164.5, 146.4, 142.9, 137.8, 133.8, 131.7, 128.2, 127.8, 127.2, 126.8, 126.7, 122.4, 118.1, 115.1, 114.4, 110.9, 75.5, 46.3 .

IR (KBr) 3297, 3090, 2944, 1727, 1625, 1483, 1383, 1323, 1242, 1191, 968.750 cm ^-1

HRMS m / z (M ⁺ ) calcd for C ₂₂ H ₁₇ N ₃ O ₂ : 355.1321. Found: 355.1318.

< Example  16> Synthesis of Compound 6f

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 10시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 82%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 10 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 82%).

mp 257-258 ° C;

¹ H NMR (300MHz, DMSO-d ₆ ) δ 10.26 (1H, s), 7.70 (1H, d, J = 7.8 Hz), 7.39 (1H, s), 7.35-7.22 (3H, m), 6.95-6.89 (3H, m), 6.81-6.71 (4H, m), 6.64 (1H, d, J = 8.1 Hz), 4.35 (1H, d, J = 15.0 Hz), 4.18 (1H, d, J = 15.3 Hz) , 2.22 (3H, s);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 174.9, 163.9, 145.9, 142.4, 135.7, 134.1, 133.2, 131.1, 128.2, 127.4, 127.3, 126.2, 121.8, 117.5, 114.6, 113.8, 110.3, 74.9, 45.4, 20.6 ;

IR (KBr) 3322, 3092, 2946, 1726, 1625, 1482, 1435, 1379, 1324, 1242, 1198, 1113, 1027, 963, 747 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₃ H ₁₉ N ₃ O ₂ : 369.1477. Found: 369.1475.

< Example  17> Synthesis of Compound 6g

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 10시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 88%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 10 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and then recrystallized from ethanol to obtain pure product (yield: 88%).

mp 227-228 ° C;

¹ H NMR (300MHz, DMSO-d ₆ ) δ 10.20 (1H, s), 7.71 (1H, d, J = 7.8 Hz), 7.37-7.22 (4H, m), 6.95 (1H, t, J = 7.8 Hz ), 6.81-6.62 (7H, m), 4.28 (2H, s), 3.68 (3H, s);

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 174.9, 163.9, 158.1, 145.9, 142.5, 133.2, 131.1, 128.9, 127.3, 126.3, 121.9, 117.5, 114.7, 113.8, 113.1, 110.4, 74.8, 54.9, 45.1 ;

IR (KBr) 3280, 3062, 2957, 1723, 1640, 1477, 1326, 1118, 1024, 944, 752 cm ^-1

HRMS m / z (M ⁺ ) calcd for C ₂₃ H ₁₉ N ₃ O ₃ : 385.1426. Found: 385.1423.

< Example  18> Synthesis of Compound 6h

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 6시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 92%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 6 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 92%).

mp 287-288 ° C;

¹ H NMR (300MHz, DMSO-d ₆ ) δ 10.56 (1H, s), 7.68 (1H, d, J = 7.5 Hz), 7.53 (1H, d, J = 7.2 Hz), 7.46-7.41 (2H, m ), 7.28-7.10 (5H, m), 6.96 (1H, d, J = 7.8 Hz), 6.80 (2H, d, J = 8.1 Hz), 6.73 (1H, t, J = 7.2 Hz), 6.63 (1H) , d, J = 7.8 Hz), 3.36 (1H, t, J = 11.4 Hz), 2.86-2.68 (2H, m), 2.57 (1H, t, J = 7.2 Hz);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 175.2, 163.3, 145.7, 142.2, 138.6, 133.2, 131.3, 128.4, 128.0, 127.2, 127.1, 126.2, 125.9, 122.4, 117.5, 114.3, 113.7, 110.6, 75.3, 44.9 , 34.2;

IR (KBr) 3279, 3062, 2956, 2873, 1723, 1639, 1513, 1477, 1394, 1325, 1272, 1234, 1189, 1023, 944, 751 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₃ H ₁₉ N ₃ O ₂ : 369.1477. Found: 369.1479.

< Example  19> Synthesis of Compound 6i

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 92%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 92%).

mp 173-175 ° C;

¹ H NMR (300MHz, DMSO-d ₆ ) δ 10.50 (1H, s), 7.62 (1H, d, J = 7.5 Hz), 7.43 (1H, d, J = 7.5 Hz), 7.37 (1H, d, J = 8.1 Hz), 7.35 (1H, s), 7.25-7.20 (3H, m), 7.14 (1H, d, J = 6.9 Hz), 7.09-7.02 (3H, m), 6.92 (1H, d, J = 7.8 Hz), 6.70 (1H, t, J = 7.2 Hz), 6.60 (1H, d, J = 8.1 Hz), 3.20 (1H, t, J = 9.3 Hz), 2.81 (1H, t, J = 9.0 Hz ), 2.33 (2H, t, J = 6.6 Hz), 1.37-1.25 (4H, m);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 175.7, 163.8, 146.1, 142.6, 142.3, 133.6, 131.7, 128.6, 127.8, 127.5, 126.2, 126.0, 122.8, 117.9, 115.0, 114.2, 111.1, 75.6, 43.1, 35.0 , 28.8, 28.1;

IR (KBr) 3260, 2935, 1726, 1689, 1624, 1400, 1365, 1325, 1191, 1030, 749 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₅ H ₂₃ N ₃ O ₂ : 397.1790. Found: 397.1794.

< Example  20> Synthesis of Compound 6j

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 91%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 91%).

mp 170-171 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.53, (1H, s), 7.66 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.5 Hz), 7.42 (1H, d, J = 7.8 Hz), 7.37 (1H, s), 7.26 (1H, t, J = 7.5 Hz) 7.12 (1H, t, J = 7.5 Hz), 6.95 (1H, d, J = 7.8 Hz), 6.72 ( 1H, t, J = 7.2Hz), 6.62 (1H, d, J = 8.1Hz), 3.17-3.07 (1H, m), 2.83-2.74 (1H, m), 1.40-1.22 (2H, m), 1.13 -1.00 (6H, m), 0.74 (3H, t, J = 6.9 Hz);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 175.8, 163.8, 146.1, 142.6, 133.5, 131.7, 127.8, 127.5, 126.3, 122.8, 117.9, 115.0, 114.2, 111.0, 75.6, 43.3, 30.9, 28.0, 26.3, 22.1 , 14.2;

IR (KBr) 3261, 2952, 2930, 2860, 1727, 1690, 1624, 1479, 1325, 1109, 1024, 943, 749 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₁ H ₂₃ N ₃ O ₂ : 349.1790. Found: 349.1793.

< Example  21> Synthesis of Compound 6k

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 89%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 89%).

mp 190-192 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.54 (1H, s), 7.66 (1H, d, J = 7.5 Hz) 7.52 (1H, d, J = 7.5 Hz), 7.39 (1H, t, J = 7.5 Hz), 7.33 (1H, s), 7.24 (1H, t, J = 7.2 Hz), 7.11 (1H, t, J = 7.5 Hz), 6.94 (1H, d, J = 7.8 Hz), 6.73 (1H , t, J = 7.2 Hz), 6.64 (1H, d, J = 7.8 Hz), 3.18-3.11 (1H, dd, J = 6.9 & 13.8 Hz), 2.79-2.71 (1H, dd, J = 7.5 & 13. 5 Hz), 1.58-1.27 (6H, m), 1.06-0.68 (5H, m);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 175.7, 164.6, 146.2, 142.6, 133.5, 131.7, 127.7, 127.6, 126.6, 122.6, 117.9, 115.3, 114.2, 110.9, 75.7, 48.9, 37.4, 31.1, 31.0, 26.3 , 26.0, 25.9;

IR (KBr) 3265, 2925, 2851, 1732, 1622, 1483, 1440, 1391, 1322, 1189, 1111, 951, 750 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₂ H ₂₃ N ₃ O ₂ : 361.1790. Found: 361.1791.

< Example  22> Synthesis of Compound 6l

(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 6시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 93%).Isatoic anhydride ( 1 ) (1.0 mmol), NH ₄ OAc (1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 6 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 93%).

mp 261-263 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.25 (1H, s), 8.30 (1H, s), 7.60 (1H, d, J = 7.5 Hz), 7.46 (1H, d, J = 6.9 Hz), 7.33 (1H, t, J = 7.5 Hz), 7.24 (1 H, s), 7.20 (1 H, d, J = 8.4 Hz), 7.05 (1 H, t, J = 6.9 Hz), 6.84 (1 H, d, J = 8.1 Hz), 6.68 (1H, t, J = 7.5 Hz), 6.61 (1H, d, J = 8.1 Hz);

_{^{13 CNMR (75MHz, DMSO- d 6}} ) δ 176.4, 164.3, 147.2, 142.5, 133.7, 131.2, 129.9, 127.3, 125.7, 122.7, 117.6, 114.8, 114.3, 110.5, 71.4;

IR (KBr) 3474, 3288, 3066, 1708, 1621, 1519, 1478, 1326, 1266, 1192, 1151, 1105, 1048, 960, 750 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₁₅ H ₁₁ N ₃ O ₂ : 265.0851. Found: 265.0847.

< Example  23> Synthesis of Compound 6m

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 8시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 93%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 8 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 93%).

mp 277-279 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.54 (1H, s), 7.74 (1H, s), 7.68 (1H, d, J = 8.4 Hz), 7.66 (1H, s), 7.35-7.18 (5H , m), 7.03 (2H, d, J = 7.8 Hz), 6.77 (1H, t, J = 6.9 Hz), 6.70 (1H, d, J = 8.1 Hz), 6.60 (1H, d, J = 8.1 Hz );

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 175.08, 163.2, 145.7, 140.9, 137.8, 133.7, 133.5, 129.4, 129.2, 128.7, 127.7, 127.4, 117.8, 117.6, 114.5, 114.09, 113.6, 112.09, 76.3;

IR (KBr) 3372, 3324, 3247, 1742, 1619, 1484, 1361, 1276, 1190, 1067, 873, 814, 750 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₁ H ₁₄ BrN ₃ O ₂ : 419.0269. Found: 419.0272.

< Example  24> Synthesis of Compound 6n

(1.0 mmol), 및 (1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 10시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 82%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 10 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 82%).

mp 275-277 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.60 (1H, s), 7.80 (1H, s), 7.70-7.66 (2H, m), 7.38-7.30 (2H, m), 7.14-7.08 (4H, m), 6.78 (1H, t, J = 7.2 Hz), 6.70 (1H, d, J = 8.4 Hz), 6.64 (1H, d, J = 8.4 Hz);

_{^{13 CNMR (75MHz, DMSO- d 6}} ) δ 173.6, 163.6, 146.0, 143.0, 134.0, 133.7, 131.0, 127.4, 126.4, 126.1, 122.8, 117.8, 115.5, 115.3, 114.3, 114.1, 108.9, 76.2.

IR (KBr) 3269, 1732, 1641, 1618, 1510, 1482, 1359, 1225, 1195, 954, 823, 750 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₁ H ₁₃ BrFN ₃ O ₂ : 437.0175. Found: 437.0174.

< Example  25> Synthesis of Compound 6o

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 10시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 90%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 10 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and then recrystallized from ethanol to obtain pure product (yield: 90%).

mp 238-240 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.70 (1H, d, J = 7.5 Hz), 7.61 (2H, d, J = 7.8 Hz), 7.34-7.13 (5H, m), 7.01 (1H, t , J = 6.9 Hz), 6.93 (2H, d, J = 7.5 Hz), 6.85 (1H, d, J = 8.1 Hz), 6.78 (1H, t, J = 7.5 Hz), 6.72 (1H, d, J = 8.1 Hz), 3.02 (3H, s);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 173.8, 163.5, 146.0, 143.1, 137.9, 133.6, 130.9, 128.6, 127.6, 127.4, 126.6, 126.1, 122.7, 117.8, 116.2, 114.5, 114.1, 108.9, 76.1, 25.9 ;

IR (KBr) 3265, 1728, 1636, 1616, 1491, 1362, 1274, 1172, 1128, 1093, 942, 884, 751 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₂ H ₁₇ N ₃ O ₂ : 355.1321. Found: 355.1318.

< Example  26> Synthesis of Compound 6p

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 8시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 92%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 8 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 92%).

mp 232-234 ° C;

¹ H NMR (300MHz, DMSO-d ₆ ) δ 7.71 (1H, d, J = 8.1 Hz), 7.60 (1H, d, J = 7.5 Hz), 7.58 (1H, s), 7.36-7.25 (2H, m ), 7.09-6.94 (3H, m), 6.87 (1H, d, J = 7.5 Hz), 6.81-6.71 (4H, m), 3.03 (3H, s), 2.15 (3H, s);

¹³ CNMR (75 MHz, DMSO-d ₆ ) δ 173.7, 163.4, 146.0, 143.1, 137.8, 133.5, 130.8, 129.5, 128.2, 128.1, 127.3, 126.6, 126.0, 122.6, 117.7, 114.5, 114.0, 108.8, 76.07, 25.8 , 20.5;

IR (KBr) 3283, 3059, 2935, 1727, 1643, 1612, 1487, 1356, 1244, 1167, 1125, 1090, 1038, 965, 872, 751 cm ⁻¹ ;

HRMS m / z (M ⁺ ) calcd for C ₂₃ H ₁₉ N ₃ O ₂ : 369.1477. Found: 369.1475.

< Example  27> Synthesis of Compound 6q

(1.0 mmol), 및

(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 8시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 88%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,

(1.0 mmol), and

EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 8 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and then recrystallized from ethanol to obtain pure product (yield: 88%).

mp 220-222 ° C;

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.68 (1H, d, J = 7.8 Hz), 7.64-7.60 (2H, m), 7.34-7.25 (2H, m), 7.05-6.95 (5H, m) , 6.86 (1H, d, J = 7.8 Hz), 6.77 (1H, t, J = 7.8 Hz), 6.69 (1H, d, J = 7.5 Hz), 3.01 (3H, s);

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 174.1, 164.1, 146.5, 143.5, 134.6, 134.5, 134.2, 131.5, 127.9, 126.9, 126.6, 123.3, 118.3, 116.1, 115.8, 114.8, 114.6, 109.5, 76.7 , 26.4;

IR (KBr) 3274, 3061, 2943, 1727, 1640, 1613, 1510, 1354, 1219, 1155, 1130, 1093, 1033, 961, 799, 752 cm ^-1

HRMS m / z (M ⁺ ) calcd for C ₂₂ H ₁₆ FN ₃ O ₂ : 373.1227. Found: 373.1227.

Claims (6)

Isatoic anhydride, amines and benzaldehydes are reacted in the presence of 20 mol% of ethylenediaminediacetate (EDDA) in water to form 2,3-dihydroquinazoli 2,3-dihydroquinazolinone derivatives are synthesized, and the amines are

,

,

,

,

,

And

Selected from the group consisting of, the benzaldehyde is

,

,

And

Synthesis method of 2,3-dihydroquinazolinone derivatives, characterized in that selected from the group consisting of:
[Formula 1]

In Formula 1, R ¹

or

X is any one of C1 to C4 alkoxy or halogen,
R ² is arylamine,

And Y ₁ is hydrogen, CH ₃ CHCH ₃ , C 1 to C 4 alkoxy or halogen, Y ₂ is hydrogen or C 1 to C 4 alkyl, and n is an integer from 0 to 4. delete delete Isatoic anhydride, amines and isatins are reacted in the presence of 20 mol% of ethylenediaminediacetate (EDDA) in water to include a dihydroquinazolinone ring represented by the formula (2). To synthesize a spirooxindole derivative, wherein the amines

,

,

,

,

,

And

Selected from the group consisting of, the isatin is

,

, And

Synthesis method of spiroxoxindole derivative comprising a dihydroquinazolinone ring, characterized in that selected from the group consisting of:
(2)

In Formula 2, R ₁

Y ₁ is hydrogen, CH ₃ CHCH ₃ , C1 to C4 alkoxy or halogen, Y ₂ is hydrogen or C1 to C4 alkyl, n is an integer from 0 to 4; C1 to C7 alkyl;

; Or hydrogen.
delete delete