KR102629506B1 - The preparation method of Piperazine-quinoline derivative, 2-ethyl-5-(4-methyl-piperazine-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dehydro-1H-quinoline-4-on - Google Patents

Abstract

The present invention is a piperazine-quinoline derivative, 2-ethyl-5-(4-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-quinoline- It relates to a method for producing 4-one, more specifically, reacting 5-chloroquinolin-4(1H)-one and naphthalen-2-sulfonyl chloride to produce 5-chloro-1-(naphthalen-2-ylsulfonyl) ) Quinolin-4(1H)-one (Compound 1) was synthesized, and the (Compound 1) was reacted with ethyl magnesium bromide (EtMgBr) to obtain 5-chloro-2-ethyl-1-(naphthalen-2-ylsulfonyl) )-2,3-dihydroquinolin-4(1H)-one (Compound 2) was synthesized, and then (Compound 2) was reacted with N-methylpiperazine to produce 2-ethyl as the target piperazine-quinoline derivative. By synthesizing -5-(4-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one (Compound 4), It relates to a method for producing a novel piperazine-quinoline derivative with simple reactants and reaction process.

Description

Piperazine-quinoline derivative as 2-ethyl-5-(4-methyl-piperazin-1-yl)-1-(naphthalen-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one The preparation method of Piperazine-quinoline derivative, 2-ethyl-5-(4-methyl-piperazine-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dehydro-1H-quinoline -4-on}

The present invention is a piperazine-quinoline derivative, 2-ethyl-5-(4-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-quinoline- It relates to a method for producing 4-one, more specifically, reacting 5-chloroquinolin-4(1H)-one and naphthalen-2-sulfonyl chloride to produce 5-chloro-1-(naphthalen-2-ylsulfonyl) ) Quinolin-4(1H)-one (Compound 1) was synthesized, and the (Compound 1) was reacted with ethyl magnesium bromide (EtMgBr) to obtain 5-chloro-2-ethyl-1-(naphthalen-2-ylsulfonyl) )-2,3-dihydroquinolin-4(1H)-one (Compound 2) was synthesized, and then (Compound 2) was reacted with N-methylpiperazine to produce 2-ethyl as the target piperazine-quinoline derivative. By synthesizing -5-(4-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one (Compound 4), It relates to a method for producing a novel piperazine-quinoline derivative with simple reactants and reaction process.

As is generally known, serotonin, or 5-hydroxytryptamine (5-HT), plays an important role in the functioning of the mammalian body, especially within the central nervous system, where 5-HT regulates sleep and eating. It is an important neurotransmitter and neuromodulator involved in a variety of behaviors and responses, such as movement, pain perception, learning and memory, sexual behavior, and regulation of body temperature and blood pressure.

Serotonin plays an important role in the control system of afferent peripheral nociceptors within the spinal column (Moulignier, Rev Neurol 1994, 150, 3-15), cardiovascular system, and hematological system. It is responsible for peripheral functions within the gastrointestinal system (GI) and gastrointestinal system (GI).

5-HT is known to mediate various contractions, secretions, and electrophysiologic effects, including vascular and non-vascular smooth muscle contraction and platelet aggregation (Fuller, Biology of Serotonergic Transmission, 1982; Boullin, Serotonin In Mental Abnormalities 1978; 1: 316; Barchas, et al, Serotonin and Behavior, 1973)

Since the wide distribution of serotonin in the body was confirmed, interest in drugs that affect the serotonin system has increased (Gershon, et al, The Peripheral Actions of 5-Hydroxytryptamine, 1989, 246; Saxena , et al, J Cardiovascular Pharmacol 1990, 15, Supp7)

Serotonin receptors are members of a large human gene family of membrane-spanning proteins that function as transducers of intercellular interactions.

Serotonin is present on the surface of various cell types, including neurons and platelets, and changes their conformational structure when activated by their endogenous ligand serotonin or by externally administered drugs. and then interact with downstream mediators of cellular signaling.

At least 15 genetically distinct 5-HT receptor subtypes have been identified and assigned to one of seven families (5-HT1-7). Each subtype exhibits a unique distribution, preference for different ligands, and functional correlation(s).

The 5-HT6 receptor, one of the serotonin receptor subtypes, is a member of the G-protein coupled receptor superfamily of serotonin receptors and, like the 5-HT4 and 5-HT7 receptors, is specifically coupled to adenylate cyclase.

In pharmacological studies, tritiated 5-HT, [ ³ H] LSD, and [ ¹²⁵ I]-2-iodinated LSD were used as radiolabeled 5-HT6 receptors. 5-HT binds with relatively high affinity (Ki=50-150 nM). Tricyclic antipsychotics and some antidepressants bind with quite high affinity. According to a related study that closely examined antipsychotics, it was found that several classes of representative antipsychotics bind with high affinity. Examples of these include phenothiazine, chloropromazine, thioxanthene, chloroprothixene, diphenylbutylpiperidine, pimozide, Heterocyclic antipsychotics include loxapine and clozapine (Roth, BL et al, J Pharmacol Exp Ther1994, 268, 1403-1410).

These results show that the 5-HT6 receptor is associated with certain types of psychosis and, in particular, may be a target for atypical antipsychotics.

Until selective ligands were developed, pharmacological studies of 5-HT6 mainly relied on the use of non-selective drugs. As no selective ligand for the receptor was present, functional studies were performed using antisense. 5-HT6-specific antisense caused specific behaviors such as yawning, stretching, and chewing in rats, but had no other obvious effects.

Although non-selective ligands were useful in pharmacological studies of the 5-HT6 system, their utility in most pharmacological studies was limited due to lack of selectivity. However, with the advent of selective drugs, great progress has been made in the research of 5-HT6. The development of more selective ligands may enable treatment with higher efficacy and lower side effects.

Additionally, selective ligands may form entirely new therapeutic approaches. The first 5-HT6-selective antagonist was announced in 1998, and subsequent research results in this field by other research teams were published one after another.

Sleight et al. reported bisaryl sulfonamide Ro 04-6790 (1, Ki = 55 nM), and Ro 63-0563 (2, Ki = 12 nM) as 5-HT6 antagonists with excellent selectivity (Sleight, A J et al. , Br J Pharmacol 1998, 124, 556-562)

Soon after, MS-245 (3, Ki = 23 nM) was released. Interestingly, although these three compounds were independent and distinct discoveries, they were all identified through random screening methods and have in common a sulfonamide bond as their core structure.

In addition, much evidence continues to be reported showing the association of 5-HT6 receptors with recognition and learning, convulsive disorders, and control of appetite. Therefore, much effort is being made to develop new 5-HT6 antagonists with superior selectivity compared to conventional drugs, and the potential of 5-HT6 receptor ligands as a treatment for central nervous system diseases is very high.

Meanwhile, 5-HT2C, one of the serotonin receptor subtypes, is transcribed and expressed in hypothalamic structures involved in appetite regulation. The 5-HT2C agonist m-chlorophenylpiperazine (mCPP), which has a preference for the 5-HT2C receptor, reduces food intake in mice expressing normal 5-HT2C receptors, while inhibiting the It has been demonstrated to be inactive in mice expressing the mutated inactivated form (Nature, 1995, 374, 542-546)

In a clinical study, after treating obese subjects with mCPP for 2 weeks, sustained weight loss occurred (Pyschopharmacology, 1997, 133, 309-312). Additionally, 5-HT2C receptors are effective in treating central nervous system (CNS) diseases such as depression and anxiety. It has been suggested to be related (IDrugs, 1999, 2, 109-120) and to urinary diseases such as urinary incontinence (IDrugs 1998, 1, 456-470)

The prior art regarding 5-HT2C receptor antagonists is as follows. US Patent Publication No. 3253989 discloses the use of mCPP as an appetite suppressant. European Patent Publication No. 863 136 discloses azetidine and pyrrolidine derivatives that are selective 5-HT2C receptor antagonists with antidepressant activity and can be used in the treatment or prevention of serotonin-related diseases, including eating disorders and anxiety. International Patent Publication No. 87/04928 discloses 2-(1-piperazinyl)pyrimidine as a treatment for neuropathy. European Patent Publication No. 226842 discloses a 1,4-naphthalenedione heterocyclic derivative containing 2-(3-bromophenyl)-4-(1-piperazinyl)pyrimidine as an anti-allergy and anti-asthmatic agent. did. European Patent Publication No. 657 426 discloses tricyclic pyrrole derivatives that have activity on 5-HT2C receptors and can be used in particular in the treatment of eating disorders. European Patent Publication No. 655 440 discloses 1-aminoenthylindole, which has activity on 5-HT2C receptors and can be used in particular for the treatment of eating disorders. European Patent Publication No. 572 863 discloses parazinoindole, which has activity on 5-HT2C receptors and can be used in particular for the treatment of eating disorders. International Patent Publication No. 00/012475 discloses an indole derivative as a 5-HT2B or 5-HT2C receptor ligand, especially for treating obesity. International Patent Publication No. 00/012510 discloses pyrroloindole, pyridoindole and azepinoindole as 5-HT2C receptor antagonists, especially for the treatment of obesity. International Patent Publication No. 00/012482 discloses indazole derivatives as selective direct active 5-HT2C receptor antagonists, particularly for use as anti-obesity agents. International Patent Publication No. 00/012502 discloses pyrroloquinoline as a 5-HT2C receptor antagonist, especially for use as an anti-obesity agent. International Patent Publication No. 00/035922 discloses 2,3,4,4,α-tetrahydro-1H-pyrazino[1,2-α]quinoxaline-5( 6H)on was started. International Patent Publication No. 00/044737 discloses aminoalkylbenzofuran, a 5-HT2C receptor antagonist that can be used to treat obesity. However, the development of 5-HT2C receptor antagonists with higher selectivity for 5-HT2C receptors is still required.

Accordingly, Korea Patent No. 10-1110199 (registration date: January 19, 2012) discloses a piperazine-quinoline derivative represented by [Formula 1], a pharmaceutically acceptable salt thereof, a method for producing it, and containing it as an active ingredient. A pharmaceutical composition has been developed for the prevention or treatment of central nervous system diseases. The resulting derivative not only has high affinity for the 5-HT6 receptor, but also acts as an antagonist for the 5-HT6 receptor and 5-HT2C receptor, thereby preventing dementia, It is known that it can be useful as a preventative or therapeutic agent for central nervous system diseases such as schizophrenia, depression, and anxiety caused by dementia.

[Formula 1]

[In Formula 1, R1 and R2 are independently hydrogen or C1-C6 linear or branched alkyl, and R3 is unsubstituted or C1-C6 linear or branched alkyl and at least one selected from the group consisting of halogen. phenyl, naphthyl, or benzothiophenyl substituted with a substituent, and X is hydrogen, halogen, or C1-C4 alkoxy, is a single or double bond, wherein In the case of a single bond, R4 is hydroxy, and in the case of a double bond, R4 is oxygen.]

However, in Korean Patent No. 10-1110199, the reaction process is complicated as it is synthesized through the first to fourth steps or the first to fifth steps, as shown in [Reaction Scheme 1] to [Reaction Scheme 4], and the reaction process is complicated and the reaction material As the number of types increased, the reaction process became difficult and there were cumbersome problems such as the need to separate and purify the target product, so a simpler manufacturing method was required.

[Scheme 1]

[Scheme 2]

[Scheme 3]

[Scheme 4]

[Patent Document 001] Korean Patent No. 10-1110199 (registration date January 19, 2012)

In order to solve the above problems, the present invention reacts 5-chloroquinolin-4(1H)-one and naphthalene-2-sulfonyl chloride to produce 5-chloro-1-(naphthalen-2-ylsulfonyl)quinoline-4. (1H)-one (Compound 1) was synthesized, and (Compound 1) was reacted with ethyl magnesium bromide (EtMgBr) to obtain 5-chloro-2-ethyl-1-(naphthalen-2-ylsulfonyl)-2, 3-Dihydroquinolin-4(1H)-one (Compound 2) was synthesized, and then (Compound 2) was reacted with N-methylpiperazine to obtain 2-ethyl-5-(as the target piperazine-quinoline derivative. Challenge to solve the method of producing 4-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one (Compound 4) Do this.

In order to solve the above problem of the present invention, 5-chloroquinolin-4(1H)-one and naphthalen-2-sulfonyl chloride are reacted to produce 5-chloro-1-(naphthalen-2-ylsulfonyl)quinoline-4( A first step of synthesizing 1H)-one (compound 1); The above (Compound 1) was reacted with ethyl magnesium bromide (EtMgBr) to produce 5-chloro-2-ethyl-1-(naphthalen-2-ylsulfonyl)-2,3-dihydroquinolin-4(1H)-one ( A second step of synthesizing compound 2); The above (Compound 2) was reacted with N-methylpiperazine to obtain 2-ethyl-5-(4-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dihydro. -3rd step of synthesizing 1H-quinolin-4-one (compound 3); 2-ethyl-5-(4-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl) )-2,3-dihydro-1H-quinolin-4-one production method as a means of solving the problem.

In the first step, tetrahydrofuran (THF), sodium hydroxide (NaOH), and 5-chloroquinolin-4(1H)-one are mixed at room temperature, stirred at 60°C, cooled to room temperature, and naphthalene-2 -Sulfonyl chloride is added, stirred at room temperature, then water is added and the above (Compound 1) is extracted with diethyl ether as a means of solving the problem.

The organic layer of the extracted diethyl ether is dried with magnesium sulfate, filtered, and then concentrated in vacuum to separate and purify the (Compound 1) as a means of solving the problem.

In the second step, (Compound 1), CuBr·SMe2 (Copper(1)bromide-dimethyl sulfide complex), and BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) are added to tichloromethane. After dissolving and stirring, ethyl magnesium bromide (EtMgBr) was slowly added and stirred, then saturated ammonium chloride solution was added and the above (Compound 2) was extracted with dichloromethane as a means of solving the problem.

The organic layer of the extracted dichloromethane is dried with magnesium sulfate, filtered, and then concentrated in vacuum to separate and purify the (Compound 2) as a means of solving the problem.

In the third step, the (compound 2), N-methylpiperazine, and potassium carbonate are dissolved in acetonitrile, subjected to a reflux stirring reaction, then a saturated ammonium chloride solution is added, and the (compound 3) is extracted with dichloromethane. as a means of solving the problem.

The organic layer of the extracted dichloromethane is dried with magnesium sulfate, filtered, and then concentrated in vacuum to separate and purify the (Compound 3) as a means of solving the problem.

Piperazine-quinoline derivative according to the present invention is 2-ethyl-5-(4-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-quinoline The method for producing -4-one is to react 5-chloroquinolin-4(1H)-one and naphthalen-2-sulfonyl chloride to produce 5-chloro-1-(naphthalen-2-ylsulfonyl)quinoline-4(1H). )-one (Compound 1) was synthesized, and the (Compound 1) was reacted with ethyl magnesium bromide (EtMgBr) to obtain 5-chloro-2-ethyl-1-(naphthalen-2-ylsulfonyl)-2,3- Dihydroquinolin-4(1H)-one (Compound 2) was synthesized, and then (Compound 2) was reacted with N-methylpiperazine to produce 2-ethyl-5-(4-) as the target piperazine-quinoline derivative. As methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one (Compound 4) is synthesized, the reactants and reaction process are It has simple and excellent advantages.

Figure 1 is a ¹ H NMR diagram of [5-chloro-1-(naphthalen-2-ylsulfonyl)quinolin-4(1H)-one (Compound 1)
Figure 2 is a ¹ H NMR diagram of 5-chloro-2-ethyl-1-(naphthalen-2-ylsulfonyl)-2,3-dihydroquinolin-4(1H)-one (Compound 2)
Figure 3 shows 2-ethyl-5-(4-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one (Compound 3 ) ¹ H NMR drawing

In the present invention, 5-chloroquinolin-4(1H)-one and naphthalen-2-sulfonyl chloride are reacted to produce 5-chloro-1-(naphthalen-2-ylsulfonyl)quinolin-4(1H)-one (compound 1) the first step of synthesizing; The above (Compound 1) was reacted with ethyl magnesium bromide (EtMgBr) to produce 5-chloro-2-ethyl-1-(naphthalen-2-ylsulfonyl)-2,3-dihydroquinolin-4(1H)-one ( A second step of synthesizing compound 2); The above (Compound 2) was reacted with N-methylpiperazine to obtain 2-ethyl-5-(4-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dihydro. -3rd step of synthesizing 1H-quinolin-4-one (compound 3); 2-ethyl-5-(4-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl) )-2,3-dihydro-1H-quinolin-4-one production method is a feature of the technical composition.

In the first step, tetrahydrofuran (THF), sodium hydroxide (NaOH), and 5-chloroquinolin-4(1H)-one are mixed at room temperature, stirred at 60°C, cooled to room temperature, and naphthalene-2 -Sulfonyl chloride is added, reaction is stirred at room temperature, water is added, and the above (Compound 1) is extracted with diethyl ether.

The technical feature is that the organic layer of the extracted diethyl ether is dried with magnesium sulfate, filtered, and then concentrated in vacuum to separate and purify the (Compound 1).

In the second step, (Compound 1), CuBr·SMe2 (Copper(1)bromide-dimethyl sulfide complex), and BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) are added to tichloromethane. After dissolving and stirring, ethyl magnesium bromide (EtMgBr) is slowly added and stirred, followed by adding saturated ammonium chloride solution and extracting the above (Compound 2) with dichloromethane.

The technical feature is that the organic layer of the extracted dichloromethane is dried with magnesium sulfate, filtered, and then concentrated in vacuum to separate and purify the (Compound 2).

In the third step, the (compound 2), N-methylpiperazine, and potassium carbonate are dissolved in acetonitrile, subjected to a reflux stirring reaction, then a saturated ammonium chloride solution is added, and the (compound 3) is extracted with dichloromethane. This is a feature of the technical composition.

The technical feature is that the organic layer of the extracted dichloromethane is dried with magnesium sulfate, filtered, and then concentrated in vacuum to separate and purify the (Compound 3).

Hereinafter, the present invention will be described in detail through examples and drawings so that those skilled in the art can easily implement the present invention. However, the present invention may be implemented in many different forms and is not limited to the embodiments and drawings described herein.

First, the 2-ethyl-5-(4-methyl-piperazin-1-yl)-1-(naphthalen-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one of the present invention. The manufacturing method is characterized in that it is manufactured by a process according to the following [reaction formula].

[Reaction formula]

That is, 5-chloroquinolin-4(1H)-one and naphthalen-2-sulfonyl chloride are reacted to produce 5-chloro-1-(naphthalen-2-ylsulfonyl)quinolin-4(1H)-one (Compound 1). A first step of synthesizing; The above (Compound 1) was reacted with ethyl magnesium bromide (EtMgBr) to produce 5-chloro-2-ethyl-1-(naphthalen-2-ylsulfonyl)-2,3-dihydroquinolin-4(1H)-one ( A second step of synthesizing compound 2); The above (Compound 2) was reacted with N-methylpiperazine to obtain 2-ethyl-5-(4-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dihydro. It is prepared according to a manufacturing method including a third step of synthesizing -1H-quinolin-4-one (compound 3).

Here, in the first step, tetrahydrofuran (THF), sodium hydroxide (NaOH), and 5-chloroquinoline-4(1H)-one are mixed at room temperature, stirred at 60°C, cooled to room temperature, and then naphthalene. After adding -2-sulfonyl chloride and stirring at room temperature, water is added and the (Compound 1) is extracted with diethyl ether.

At this time, the extracted organic layer of diethyl ether was dried with magnesium sulfate, filtered, and concentrated in vacuum to separate and purify the (Compound 1).

In addition, in the second step, (Compound 1), CuBr·SMe2 (Copper(1)bromide-dimethyl sulfide complex) and BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) are reacted with thichloro. After dissolving in methane and stirring, ethyl magnesium bromide (EtMgBr) was slowly added and stirred, then saturated ammonium chloride solution was added, and the above (Compound 2) was extracted with dichloromethane.

At this time, the extracted organic layer of dichloromethane is dried with magnesium sulfate, filtered, and concentrated in vacuum to separate and purify the (Compound 2).

Additionally, in the third step, the (Compound 2), N-methylpiperazine, and potassium carbonate were dissolved in acetonitrile, subjected to a reflux stirring reaction, then a saturated ammonium chloride solution was added, and the (Compound 3) was reacted with dichloromethane. Extract.

At this time, the extracted organic layer of dichloromethane is dried with magnesium sulfate, filtered, and concentrated in vacuum to separate and purify the (Compound 3).

[Preparation of 5-chloro-1-(naphthalen-2-ylsulfonyl)quinolin-4(1H)-one (Compound 1)]

After forming a mixed solution by mixing NaOH (3.46 g, 86.5 mol: 60wt% in mineral oil) in THF (150 ml) at room temperature, 5-chloroquinolin-4(1H)-one (5.59 g, 31.1 mol) was dissolved and added to the mixture and stirred at 60°C for 15 minutes.

After cooling to room temperature, naphthalene-2-sulfonyl chloride (10.5 g, 46.3 mol) was added and stirred at room temperature for 12 hours. After the reaction was completed, water was added and extracted with diethyl ether. The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo. The organic residue was chromatographed on silica gel to obtain (Compound 1) (8.88 g, 24.0 mol: 77% yield). Synthesis confirmation ¹ H NMR is shown in [Figure 1].

^1H NMR (500 MHz, CDCl ₃ ) δ 8.82 (d, J = 4.5Hz, 1H), 8.55-8.51 (m, 1H), 8.03-7.93 (m, 5H), 7.73-7.64 (m, 2H), 7.59-7.55 (m, 2H), 7.37-7.33 (m, 1H).

MS(EI) m/e 369[M ⁺ ]

[Preparation of 5-chloro-2-ethyl-1-(naphthalen-2-ylsulfonyl)-2,3-dihydroquinolin-4(1H)-one (Compound 2)]

The above (Compound 1) (740 mg, 2.0 mol), CuBr·SMe2 (21 mg, 5 mol%) and BINAP (74 mg, 6 mol%) were dissolved in dichloromethane (20 ml) and then stirred for 20 minutes under nitrogen at room temperature. It was stirred for a minute. Ethylmagnesium bromide (EtMgBr) (2.0 M in Et ₂ O 2ml, 4.0 mol) was slowly added to the reaction mixture at 0°C and stirred at 0°C for 2 hours. After the reaction was completed, saturated ammonium chloride solution was added, and extraction was performed with dichloromethane. The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo. The organic residue was chromatographed on silica gel to obtain (Compound 2) (240 mg, 0.6 mol: 30% yield). Synthesis confirmation ¹ H NMR is shown in [Figure 2].

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.90-7.85 (m, 4H), 7.69-7.60 (m, 2H), 7.51-7.46 (m, 2H), 7.36-7.34 (m, 1H), 4.57-4.53 (m, 1H). 2.45-2.28 (m, 2H), 1.63-1.49 (m, 2H), 0.98-0.96 (m, 3H).

MS(EI) m/e 399[M ⁺ ]

[2-Ethyl-5-(4-methyl-piperazin-1-yl)-1-(naphthalen-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one (Compound 3) manufacturing]

The above (Compound 2) (800 mg, 2.0 mol), N-methylpiperazine (0.35 ml, 3.0 mol), and potassium carbonate (830 mg, 6.0 mol) were dissolved in acetonitrile (20 ml) and refluxed for 4 hours. r I fell in love. After the reaction was completed, saturated ammonium chloride solution was added, and extraction was performed with dichloromethane. The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo. The organic residue was chromatographed on silica gel to obtain (Compound 3) (650 mg, 1.4 mol: 70% yield). Synthesis confirmation ¹ H NMR is shown in [Figure 3].

^1H NMR (500 MHz, CDCl ₃ ) δ 8.19 (s, 1H), 7.86-7.82 (m, 3H), 7.64-7.43 (m, 5H), 6.95 (d, J = 8.0 Hz, 1H), 4.55- 4.53 (m, 1H), 2.94-2.88 (m, 4H), 2.56-2.40 (m, 5H). 2.31 (s, 3H), 2.23-2.20 (m, 1H), 1.69-1.62 (m, 1H), 1.60-1.45 (m, 1H), 1.00-0.96 (m, 3H).

MS(EI) m/e 463[M ⁺ ]

The above description is merely an illustrative explanation of the technical idea of the present invention, and various modifications and variations will be possible to those skilled in the art without departing from the essential characteristics of the present invention. Accordingly, the embodiments and drawings disclosed in the present invention are not intended to limit the technical idea of the present invention, but are for illustrating, and the scope of the technical idea of the present invention is not limited by these embodiments and drawings. The scope of protection of the present invention should be interpreted in accordance with the claims below, and all technical ideas within the equivalent scope should be construed as being included in the scope of rights of the present invention.

Claims (7)

5-Chloroquinolin-4(1H)-one and naphthalen-2-sulfonyl chloride are reacted to produce 5-chloro-1-(naphthalen-2-ylsulfonyl)quinolin-4(1H)-one (Scheme 1 below) A first step of synthesizing; The above (Compound 1) was reacted with ethyl magnesium bromide (EtMgBr) to produce 5-chloro-2-ethyl-1-(naphthalen-2-ylsulfonyl)-2,3-dihydroquinolin-4(1H)-one ( A second step of synthesizing compound 2) in the following reaction scheme; The above (Compound 2) was reacted with N-methylpiperazine to obtain 2-ethyl-5-(4-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dihydro. 2-ethyl-5-(4-methyl-piperazin-1-yl)-1-(characterized by comprising a third step of synthesizing -1H-quinolin-4-one (compound 3 in the following scheme); Method for producing naphthalen-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one
[Reaction formula]

According to paragraph 1,
In the first step, tetrahydrofuran (THF), sodium hydroxide (NaOH), and 5-chloroquinolin-4(1H)-one are mixed at room temperature, stirred at 60°C, cooled to room temperature, and naphthalene-2 -2-Ethyl-5-(4-methyl-piperazine-1), characterized in that sulfonyl chloride is added, reaction is stirred at room temperature, water is added, and the above (Compound 1) is extracted with diethyl ether. Method for producing -1-(naphthalen-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one
According to paragraph 2,
2-Ethyl-5-(4-methyl-piperazine-1), characterized in that the organic layer of the extracted diethyl ether is dried with magnesium sulfate, filtered, and then concentrated in vacuum to separate and purify the (Compound 1). Method for producing -1-(naphthalen-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one
According to paragraph 1,
In the second step, (Compound 1), CuBr·SMe2 (Copper(1)bromide-dimethyl sulfide complex), and BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) are added to tichloromethane. After dissolving and stirring, ethyl magnesium bromide (EtMgBr) was slowly added and stirred, saturated ammonium chloride solution was added, and the above (Compound 2) was extracted with dichloromethane. 2-ethyl-5-(4) Method for producing -methyl-piperazin-1-yl)-1-(naphthalen-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one
According to paragraph 4,
The organic layer of the extracted dichloromethane was dried with magnesium sulfate, filtered, and then concentrated in vacuum to separate and purify the (Compound 2). 2-Ethyl-5-(4-methyl-piperazine-1-) 1) Method for producing -1-(naphthalen-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one
According to paragraph 1,
In the third step, the (compound 2), N-methylpiperazine, and potassium carbonate are dissolved in acetonitrile, subjected to a reflux stirring reaction, then a saturated ammonium chloride solution is added, and the (compound 3) is extracted with dichloromethane. Preparation of 2-ethyl-5-(4-methyl-piperazin-1-yl)-1-(naphthalen-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one, characterized in that method
According to clause 6,
The organic layer of the extracted dichloromethane was dried with magnesium sulfate, filtered, and concentrated in vacuum to separate and purify the (Compound 3). 2-Ethyl-5-(4-methyl-piperazine-1-) 1) Method for producing -1-(naphthalen-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one