KR100563187B1 - The method for preparing 7-substituted quinoline-5,8-dione derivatives - Google Patents

Abstract

The present invention provides a method for preparing 7-substituted quinoline-5,8-dione derivatives. Specifically, the present invention provides a method for preparing 7-substituted quinoline-5,8-dione derivatives by reacting 6 or 7-halo quinoline-5,8-dione with nucleophiles.

In the preparation method according to the invention, 7-substituted quinolin-5,8-dione derivatives can be prepared as products by using 6 or 7-halo quinoline-5,8-dione as an intermediate. In particular, 7-substituted quinoline-5,8-dione derivatives can be prepared in high yield using 6-halo quinoline-5,8-dione as an intermediate.

Quinoline-5,8-dione

Description

The method for preparing 7-substituted quinoline-5,8-dione derivatives {THE METHOD FOR PREPARING 7-SUBSTITUTED QUINOLINE-5,8-DIONE DERIVATIVES}

The present invention provides a method for preparing 7-substituted quinoline-5,8-dione derivatives. Specifically, the present invention provides a method for preparing 7-substituted quinoline-5,8-dione derivatives by reacting 6 or 7-halo quinoline-5,8-dione with a nucleophilic agent.

Quinoline-5,8-dione derivatives have various pharmacological actions such as anticancer action, antibacterial action, antifungal action or antimalarial action and thus are used as important substances for the development of drugs such as antifungal agents [Porter, TH Bowman, CM, Folkers, K., J. Med. Chem. , 1973 , 16 , 115; Take, Y., Oogose, K., Kubo, T., Inouye, Y., J. Antibiot , 1987 , 40 , 679; Lazo, JS, Aslan, DC, Southwick, EC, Cooley, KA, Ducruet, AP, Joo, B., Vogt, A., Wipf, P., J. Med. Chem. , 2001 , 44 , 4042]. In particular, the antifungal and antimalarial effects of quinoline-5,8-dione are known to be due to the inhibition of the mitochondrial electron transport system ( Arch, Biochem, Biophys, 1978 , 191 , 306-315), quinoline-5, 8-dione derivatives exhibit antifungal action by inhibiting Co-Q dependent succinate oxidase electron transfer of fungal mitochondria, or by producing peroxides in the process [ J. Med. Chem., 1973 , 16 , 206-209]. In addition, the results of searching for the antifungal action of quinoline-5,8-dione derivatives have been published [ Arch, Pharm, Res. , 1994 , 17 , 139-144.

Among the quinoline-5,8-dione derivatives, 7-alkylaminoquinoline- 5,8- dione represented by the following formula (1) is an anticancer activity of Streptonigrine , Steptonigrone , and Lavendamycin . It is known to be the most important compound to determine the activity [Rao, KV, Cancer Chemother. Rep., 1974 , 4 , 1].

(R _a R _b N- of Formula 1 R _a or R _b is selected from hydrogen, a straight or cyclic alkyl group of C _{1 to} C ₇ and a substituted or unsubstituted aryl group, or -NR _a R _b is a branched ring of C ₁ to C ₂ Amine group or C _{1 to} C ₇ cyclic amine group)

On the other hand, research on the preparation of quinoline-5,8-dione derivatives has been in progress for a long time.

Bracher published a method for the production of quinoline-5,8-dione by oxidation of 5-amino-8-hydroxyquinoline with dichromate. However, 5-amino-8-hydroxyquinoline, which is used as a starting material, requires a dual functionalization of the quinoline nucleus, which is an expensive and not readily available material ( Heterocycles , 1989 , 29 , 2093).

In addition, in the structure of the quinaldine-5,8-dione derivative, quinaldine- has a substituent on carbon-2, carbon-3, and carbon-4, and has hydrogen on carbon-6 and carbon-7. A method for preparing 5,8-dione derivatives is obtained by photooxidizing 8-hydroxyquinoline having substituents at carbon-2, carbon-3 and carbon-4 in the presence of a photosensitive agent to obtain an intermediate hydroxyperoxide. It is known to prepare and to produce a quinaldine-5,8-dione derivative by decomposing the resulting hydroxy peroxide (Public Patent No. 2002-7001774).

In addition, 6, which has a substituent on carbon-2 in the presence of an organic base such as triethylamine or diisopropylethylamine by the method of preparing 6-halo-7-aziridinyl quinaldine-5,8-dione, It is known to prepare 6-halo-7-aziridinyl quinaldine-5,8-dione by reacting 7-dihalo quinaldine-5,8-dione with an aziridinyl-based compound (Patent 1983- 4604). However, in the above method, 7-halo-6-aziridinyl quinaldine-5,8-dione is produced as a by-product, and 7-halo-6-aziridinyl quinaldine-5,8-dione is produced as a by-product. Silver is similar in structure to 6-halo-7-aziridinyl quinaldine-5,8-dione and cannot be easily purified.

In addition, 6,7-dihalo is a method for producing 6-phenylamino-7-haloquinoline-5,8-dione, which is used as an active ingredient of an antifungal agent due to its excellent antifungal activity against fungi infecting humans and animals. A method of preparing 6-phenylamino-7-haloquinoline-5,8-dione by reacting quinoline-5,8-dione with aryl amine is known (Patent Publication 1999-16076). However, when the alkylation reagent is reacted with 6,7-dihaloquinoline-5,8-dione, it is more reactive with carbon-6 than carbon-7 and generally 6-substituted quinoline-5,8-dione. Is generated.

Therefore, in order to prepare the 7-substituted quinoline-5,8-dione derivative represented by the formula (1) should be used a new manufacturing method.

The present invention provides a method for preparing 7-substituted quinoline-5,8-dione derivatives.

The present invention provides a method for preparing 7-substituted quinoline-5,8-dione derivatives.

The preparation method of the 7-substituted quinoline-5,8-dione derivative according to the present invention is briefly shown in Scheme 1 below.

Wherein R ₁ , R ₂ and R ₃ are methyl groups or hydrogen; X is halogen and halogen is bromine, chlorine or iodine; R is R ₄ -O, R ₄ -S or R ₅ R ₆ -N wherein R ₄ is a C ₁ to C ₆ chain or cyclic alkyl group or C _{4 to} C ₆ Substituted or unsubstituted aryl group; And R ₅ R ₆ -N is a piperidinyl group, methylaziridinyl group, benzyl amine group, n-butyl amine group, cyclohexyl amine group, cyclopentyl amine group, t-butyl amine group, amino group and 4-chloroaniline group Selected from the group consisting of

In the above, preferably R ₁ is a methyl group; R ₂ and R ₃ are hydrogen; X is halogen wherein halogen is bromine, chlorine or iodine and preferably bromine; R is R ₅ R ₆ -N wherein R ₅ R ₆ -N is a piperidinyl group, methylaziridinyl group, benzyl amine group, n-butyl amine group, cyclohexyl amine group, cyclopentyl amine group, t-butyl It is selected from the group consisting of an amine group, an amino group and a 4-chloroaniline group.

1.Method for Preparing Compound of Formula 2

A method for preparing a compound represented by Chemical Formula 2 from the compound represented by Chemical Formula 1 in Scheme 1 is shown in Scheme 2 below.

Wherein R ₁ , R ₂ and R ₃ are as described in Scheme 1 above; X is halogen wherein halogen is bromine, chlorine or iodine and preferably bromine; halogenated reagents are bromine, chlorine Or iodine; the oxidizing agent is nitric acid)

Specifically, the method for preparing a compound represented by Formula 2 according to the present invention,

(1) preparing a compound represented by Chemical Formula 6 by reacting a halogenated reagent with a compound represented by Chemical Formula 1 (step 1); And

(2) preparing a compound represented by Chemical Formula 2 by reacting the compound represented by Chemical Formula 6 with an oxidizing agent (Step 2).

(Step 1)

Step 1 is a step of preparing a compound represented by Chemical Formula 6 by reacting a halogenation reagent with a compound represented by Chemical Formula 1. In the above, the halogenating reagent is selected from the group consisting of bromine (Bromine, Br ₂ ), chlorine (Chlorine, Cl ₂ ) or iodine (Iodine, I ₂ ), and the reaction solvent uses alcohol, preferably methanol. And reaction temperature is made into normal temperature.

(Step 2)

Step 2 is a step of reacting an oxidizing agent with the compound represented by Chemical Formula 6. In the above, the oxidizing agent uses nitric acid.

2. Process for preparing compound of formula 4

The method for preparing the compound of Formula 4 in Scheme 1 is shown in Scheme 3 below.

Wherein R ₁ , R ₂ and R ₃ are as described in Scheme 1 above; X is halogen wherein halogen is bromine, chlorine or iodine, preferably bromine; and halogenating reagent is N- Bromosuccinimide, N-chlorosuccinimide, N-iodinesuccinimide, bromine, chlorine and iodine)

In the preparation method according to the present invention, the compound represented by the formula (4) may be prepared by reacting the compound represented by the formula (3) with a halogenation reagent in the presence of acetic anhydride.

The halogenated reagent is N-Bromosuccinimide (NBS), N-Chlorosuccinimide (NCS), N-Iodosuccinmide (NIS), bromine ( Bromine, Br ₂ ), chlorine (Chlorine, Cl ₂ ) and iodine (Iodine, I ₂ ), the reaction solvent may be used tetrahydrofuran or methylene chloride.

In addition, the reaction mechanism of the compound represented by the formula (3) and the nucleophile in the presence of acetic anhydride in the reaction scheme 3 is shown in Scheme 4 below.

(Wherein R ₁ , R ₂ and R ₃ are as described in Scheme 1 above; X is halogen wherein halogen is bromine, chlorine or iodine, preferably bromine)

As shown above, the hydroxy group at carbon-8 in the compound represented by Formula 3 is more easily alkoxy than the hydroxy group at carbon-5 due to the internal nature of nitrogen-1 (states of formula a and b). It can be an ion and quickly acetylated (state of formula c). Thus, 5-hydroxy-8-acetoxy quinolin-5,8-dione, a compound represented by the formula (c), is produced as an intermediate.

Meanwhile, in the compound represented by Formula (c), the acetoxy group of carbon-8 prevents the carbon-7 from reacting with the halogenated reagent due to steric hinderance, so that the halogenated reagent may react selectively with carbon-6. (State of formula d). In addition, a compound represented by Chemical Formula 4 may be selectively generated through an oxidation reaction.

In addition, the compound represented by the formula (1) used as a starting material in Scheme 3 can be prepared by a known method using 2,5-dimethoxyaniline. For example, in the compound represented by Chemical Formula 1, R ₁ is a methyl group and R ₂ and R ₃ are hydrogen, as shown in Scheme 5 below, 2,5-dimethoxyaniline and 2,5-dimethoxyaniline are concentrated. It may be prepared by reacting crotonaldehyde with a mixture of bromic acid.

3. Process for preparing the compound of formula 5

The method for preparing the compound of Formula 5 according to the present invention is shown in Scheme 6 below.

(Wherein R ₁ , R ₂ , R _3, X and R are as defined in Scheme 1 above, in R ₄ -OH and R ₄ -SH, R ₄ is C ₁ -C ₆ chain or cyclic) Of an alkyl group or C _{4 to} C ₆ Substituted or unsubstituted aryl group; And R ₅ in R ₆ -NH R ₅ R ₆ -N is a piperidino group, a methyl-aziridinyl group, a benzyl amine, n- butyl amine, cyclohexyl amine, cyclopentyl amine, t- butyl amine group, Amino group and 4-chloroaniline group).

The method for preparing the compound of Formula 5 according to the present invention may be prepared by reacting a compound represented by Formula 2 or Formula 4 with nucleophile R ₅ R ₆ -NH, R ₄ -OH, or R ₄ -SH. Specifically, when the compound represented by the formula (5) is prepared from the compound represented by the formula (2) or (4) according to the present invention, the reaction solvent is methanol, dioxane, benzene or methylene chloride, and the reaction temperature is room temperature. The reaction time may be adjusted depending on the reactivity of the alkylation reagent, but may be 10 minutes to 72 hours. In addition, in order to increase the regioselectivity of the reaction to increase the production rate of the compound represented by Formula 5 in the scheme, it is preferable to add a large amount of base, and triethylamine may be used as the base.

The method for preparing the compound represented by Formula 5 according to the present invention reduces the production of 6-substituted quinoline-5,8-dione by increasing the reactivity of carbon-7 in the compound represented by Formula 2 or 4, The production rate of substituted quinoline-5,8-dione was increased.

Specifically, R ₅ R ₆ -NH, R ₄ -OH or R ₄ -SH is reacted with 6,7-dihaloquinoline-5,8-dione used as an intermediate in the preparation of quinoline-5,8-dione derivatives. 6-substituted 7-halo quinoline-5,8-dione was produced as the main product. In addition, the 7-substituted 6-halo quinoline-5,8-dione produced as a by-product in the above method was difficult to separate because the structure is similar to the 6-substituted 7-halo quinoline-5,8-dione, 7 To prepare the compound of formula 5 from -substituted 6-haloquinoline-5,8-dione, a separate reaction must be carried out to remove halogen of carbon-6.

However, in the preparation method according to the present invention, the compound represented by the formula (5) can be produced as a product by using the compound represented by the formula (2) or (4) as an intermediate, and a reaction for removing the carbon-6 halogen is further required. There is no.

In particular, when the compound represented by the formula (4) in which carbon-6 is halogen is used as an intermediate, the compound represented by the formula (5) can be prepared in high yield.

Hereinafter, the present invention will be described in detail by way of examples. However, the present invention is not limited by the following examples.

<Example 1>

Synthesis of 6-bromoquinoline-5,8-dione

Croton aldehyde (14 mL, 11.84 g, 169 mmol) was added to a mixture of 2,5-dimethoxy aniline (20 g, 130 mmol) and 150 mL concentrated bromic acid. The reaction mixture was then refluxed for 24 hours. After the reaction was completed, sodium hydrogen carbonate was added to the reaction mixture to neutralize the reaction mixture, extracted with ethyl acetate, and then concentrated under reduced pressure to remove the solvent to obtain a residue. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 2: 3 (volume ratio)) to give 5,8-dihydroxyquinoline (7.4 g, 42.4 mmol) in a yield of 32.5%.

5,8-dihydroxyquinoline:

¹ H NMR (200 MHz, CDCl ₃ + DMSO-d ₆ ): δ 8.41 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 2.70 (d, J = 8.4 Hz, 1H)

¹³ C NMR (50 MHz, CDCl ₃ + DMSO-d ₆ ): δ 156.6, 144.8, 144.1, 137.4, 131.3, 120.8, 118.0, 108.9, 107.9, 24.6

MS (EI) 175 (M ⁺ , 100), 146, 118, 87, 74, 52, 39

The obtained 5,8-dihydroxyquinoline (1.0 g, 5.57 mmol) was dissolved in a mixed solvent of 40 ml of methylene chloride and 10 ml of tetrahydrofuran, and 2 ml of acetic anhydride was added. The mixture was stirred at room temperature for 5 minutes, then NBS (1.7 g, 9.55 mmol) was added and reacted for 10 minutes. After the reaction was completed, an aqueous solution containing 3 g of sodium hydrogen carbonate was added, extracted with methylene chloride, and concentrated under reduced pressure to remove the solvent to obtain a residue. The residue thus obtained was purified by column chromatography (ethyl acetate: hexane = 2: 3 (volume ratio)) to obtain a target compound (1.23 g, 4.89 mmol) in an yield of 85.7%.

¹ H NMR (200 MHz, CDCl ₃ ): δ 8.39 (d, J = 8.4 Hz, 1H), 7.65 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 2.80 (s, 3H)

¹³ C NMR (50 MHz, CDCl ₃ + DMSO-d ₆ ): δ 178.6, 175.1, 163.3, 144.3, 137.8, 137.0, 133.3, 125.4, 123.7, 22.9

MS (EI) 253 (M ⁺ , 100), 251 (M ⁺ , 100), 225, 223, 197, 195, 144, 116, 89, 63, 53, 39

Anal. Calcd for C ₁₀ H ₆ BrNO ₂ : C, 47.65; H, 2.40; N, 5.56. Found: C, 47.40; H, 2.55; N, 5.53

<Example 2>

Synthesis of 7-methylaziridinylquinoline-5,8-dione

6-Bromoquinoline-5,8-dione (200 mg, 0.79 mmol) prepared in Example 1 was dissolved in a mixture of 10 ml of methylene chloride and 10 ml of triethylamine. Then 0.19 ml of methylaziridine was added dropwise at room temperature. The reaction mixture was stirred for 15 minutes, then 100 ml of water was added, extracted with methylene chloride, dried over sodium sulfate and concentrated under reduced pressure to give a residue. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 2: 3 (volume ratio)) to give the title compound in a yield of 94%.

mp 106-107 ℃

¹ H NMR (200 MHz, CDCl ₃ ): δ 8.03 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 6.14 (s, 1H), 2.64 (s, 3H), 2.25-2.40 (m, 1H), 2.10-2.20 (m, 2H), 1.37 (d, J = 5.4 Hz, 3H)

¹³ C NMR (50 MHz, CDCl ₃ ): δ 183.4, 180.0, 163.7, 157.8, 146.6, 134.0, 127.4, 126.9, 117.4, 36.3, 34.4, 24.8, 17.3

MS (CI) 229 (M ⁺ +1), 215, 201, 189, 57, 43

HRMS m / z (EI) 228.0917, calcd for C ₁₃ H ₁₂ N ₂ O ₂ 228.0899

<Example 3>

Synthesis of 7-benzylaminoquinoline-5,8-dione

Except for using benzyl amine instead of methyl aziridine in Example 2 was carried out in the same manner as in Example 2 to obtain the target compound in 87% yield.

¹ H NMR (200 MHz, CDCl ₃ ): δ 8.29 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.28-7.40 (m, 5H), 6.42 (bs, 1H ), 5.80 (s, 1 H), 4.41 (d, J = 6.0 Hz, 1 H), 2.73 (s, 3 H)

¹³ C NMR (50 MHz, CDCl ₃ ): δ 182.0, 180.4, 163.0, 147.9, 146.1, 135.6, 134.5, 129.0, 128.4, 128.2, 127.6, 100.9, 46.9, 29.6, 24.9

MS (EI) 278 (M ⁺ ), 276, 261, 194, 174, 117, 91 (100), 77, 65, 51, 39

<Example 4>

Synthesis of 7-n-butylaminoquinoline-5,8-dione

Except for using n-butyl amine instead of methyl aziridine in Example 2 was carried out in the same manner as in Example 2 to obtain the target compound in 93% yield.

mp 139-140 ° C

¹ H NMR (200 MHz, CDCl ₃ ): δ 8.31 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 6.06 (bs, 1H), 5.75 (s, 1H), 3.22 (q, J = 6.7 Hz, 2H), 2.73 (s, 3H), 1.60-1.80 (m, 2H), 1.35-1.58 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H)

¹³ C NMR (50 MHz, CDCl ₃ ): δ 181.7, 180.4, 162.7, 148.1, 146.1, 133.3, 128.6, 128.1, 99.8, 42.4, 30.1, 24.8, 20.1, 13.6

MS (EI) 244 (M ⁺ ), 215, 201, 189, 174, 161, 146, 117, 92, 65, 41

Anal. Calcd for C ₁₄ H ₁₆ N ₂ O ₂ : C, 68.83; H, 6.60; N, 11.47. Found: C, 69.16; H, 6.98; N, 11.62

<Example 5>

Synthesis of 7-cyclohexylaminoquinoline-5,8-dione

Except for using cyclohexylamine instead of methyl aziridine in Example 2 was carried out in the same manner as in Example 2 to obtain the target compound in 74% yield.

mp 208-209 ° C

¹ H NMR (200 MHz, CDCl ₃ ): δ 8.30 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 5.97 (bd, J = 7.8 Hz, 1H), 5.78 ( s, 1H), 3.20-3.40 (m, 1H), 2.73 (s, 1H), 1.95-2.15 (m, 2H), 1.22-1.44 (m, 5H)

¹³ C NMR (50 MHz, CDCl ₃ ): δ 181.7, 180.5, 162.7, 146.9, 146.2, 134.3, 128.6, 128.0, 99.9, 51.4, 31.8, 25.4, 24.8, 24.5

MS (EI) 270 (M ⁺ ), 253, 227 (100), 189, 161, 117, 92, 55, 41

HRMS m / z (EI) 270.1374, calcd for C ₁₆ H ₁₈ N ₂ O ₂ 270.1368

<Example 6>

Synthesis of 7-cyclopentylaminoquinoline-5,8-dione

A target compound was obtained in a yield of 74% by the same method as Example 2 except for using cyclopentylamine instead of methylaziridine in Example 2.

mp 178-179 ℃

¹ H NMR (200 MHz, CDCl ₃ ): δ 8.31 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 5.99 (bs, 1H), 5.78 (s, 1H), 3.75-3.95 (m, 1H), 2.74 (s, 1H), 1.95-2.13 (m, 2H), 1.60-1.85 (m, 6H)

¹³ C NMR (50 MHz, CDCl ₃ ): δ 181.6, 180.5, 162.7, 147.6, 146.2, 134.3, 128.6, 128.0, 100.0, 54.0, 32.6, 24.8, 24.0

MS (EI) 256 (M ⁺ , 100), 227, 213, 189, 161, 117, 92, 55, 41

Anal. Calcd for C ₁₅ H ₁₆ N ₂ O ₂ : C, 70.29; H, 6.29; N, 10.93. Found: C, 70.41; H, 6.62; N, 10.95

<Example 7>

Synthesis of 7-t-butylaminoquinoline-5,8-dione

Except for using methyl t-butyl amine instead of methyl aziridine in Example 2 was carried out in the same manner as in Example 2 to obtain the target compound in 48% yield.

mp 142-144 ° C

¹ H NMR (200 MHz, CDCl ₃ ): δ 8.30 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 6.08 (bs, 1H), 5.99 (s, 1H), 2.73 (s, 3H), 1.47 (s, 9H),

¹³ C NMR (50 MHz, CDCl ₃ ): δ 181.4, 180.8, 162.7, 146.0, 134.2, 128.3, 128.0, 101.8, 51.8, 28.2, 24.8

MS (EI) 244 (M ⁺ ), 229, 221, 188, 161 (100), 132, 107, 93, 57, 41

HRMS m / z (EI) 244. 1214, calcd for C ₁₄ H ₁₆ N ₂ O ₂ 244.1212

<Example 8>

Synthesis of 7-aminoquinoline-5,8-dione

Except for using ammonia water (NH ₄ OH) in place of methyl aziridine in Example 2 was carried out in the same manner as in Example 2 to obtain the target compound in 34% yield.

Example 9

Synthesis of 7- (4-chloroaniline) aminoquinoline-5,8-dione

A target compound was obtained in a yield of 11% by the same method as in Example 2, except that 4-chloroaniline was used instead of methylaziridine in Example 2.

<Example 10>

Synthesis of 7-methoxyquinoline-5,8-dione

Except for using methyl aziridine in Example 2, except that methanol was carried out in the same manner as in Example 2 to obtain the target compound in 11% yield.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.30 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 6.21 (s, 3H), 3.95 (s, 3H), 2.78 (s, 3 H)

¹³ C NMR (100 MHz, CDCl ₃ ): δ 183.7, 178.4, 164.5, 160.7, 146.3, 134.4, 127.9, 126.9, 109.1, 56.6, 25.1

MS (EI) 203 (M ⁺ , 100), 174, 145, 132, 117, 104, 77, 64, 53, 39

Anal. Calcd for C ₁₁ H ₉ NO ₃ : C, 65.02; H, 4.46; N, 6.89. Found: C, 65.02; H, 4.49; N, 7.17

<Example 11>

Synthesis of 7-piperidinylaminoquinoline-5,8-dione (1)

6-Bromoquinoline-5,8-dione (200 mg, 0.79 mmol) prepared in Example 1 was dissolved in 10 ml of dioxane. Then, 0.19 ml of piperidine was added dropwise at room temperature. The reaction mixture was stirred for 10 minutes, then 100 mL of water was added, extracted with methylene chloride, dried over sodium sulfate, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 2: 3 (volume ratio)) to give the title compound in a yield of 70%.

mp 157-158 ℃

¹ H NMR (200 MHz, CDCl ₃ ): δ 8.24 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 6.01 (s, 1H), 3.56 (bs, 4H), 2.73 (s, 3H), 1.73 (bs, 6H)

¹³ C NMR (50 MHz, CDCl ₃ ): δ 182.1, 182.0, 162.9, 154.0, 148.0, 133.8, 127.5, 126.9, 108.3, 50.4, 25.7, 24.9, 24.2

MS (EI) 256 (M ⁺ , 100), 227, 213, 189, 161, 145, 117, 101, 84, 41

Anal. Calcd for C ₁₅ H ₁₆ N ₂ O ₂ : C, 70.29; H, 6.29; N, 10.93. Found: C, 70.07; H, 6.61; N, 11.11

<Example 12>

Synthesis of 7-piperidinylaminoquinoline-5,8-dione (2)

Except for using benzene instead of dioxane in Example 11 and the same method as in Example 11 to obtain the target compound in 75% yield.

mp 157-158 ℃

¹ H NMR (200 MHz, CDCl ₃ ): δ 8.24 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 6.01 (s, 1H), 3.56 (bs, 4H), 2.73 (s, 3H), 1.73 (bs, 6H)

¹³ C NMR (50 MHz, CDCl ₃ ): δ 182.1, 182.0, 162.9, 154.0, 148.0, 133.8, 127.5, 126.9, 108.3, 50.4, 25.7, 24.9, 24.2

MS (EI) 256 (M ⁺ , 100), 227, 213, 189, 161, 145, 117, 101, 84, 41

Anal. Calcd for C ₁₅ H ₁₆ N ₂ O ₂ : C, 70.29; H, 6.29; N, 10.93. Found: C, 70.07; H, 6.61; N, 11.11

Example 13

Synthesis of 7-piperidinylaminoquinoline-5,8-dione (3)

Except for using dimethylene chloride instead of dioxane in Example 11 was carried out in the same manner as in Example 11 to obtain the target compound in 88% yield.

mp 157-158 ℃

¹ H NMR (200 MHz, CDCl ₃ ): δ 8.24 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 6.01 (s, 1H), 3.56 (bs, 4H), 2.73 (s, 3H), 1.73 (bs, 6H)

¹³ C NMR (50 MHz, CDCl ₃ ): δ 182.1, 182.0, 162.9, 154.0, 148.0, 133.8, 127.5, 126.9, 108.3, 50.4, 25.7, 24.9, 24.2

MS (EI) 256 (M ⁺ , 100), 227, 213, 189, 161, 145, 117, 101, 84, 41

Anal. Calcd for C ₁₅ H ₁₆ N ₂ O ₂ : C, 70.29; H, 6.29; N, 10.93. Found: C, 70.07; H, 6.61; N, 11.11

<Example 14>

Synthesis of 7-bromoquinoline-5,8-dione

(Step 1): Synthesis of 5,7-dibromo-8-hydroxyquinoline

A bromine solution was prepared by dissolving 10 ml bromine in 100 ml methanol. The bromine solution prepared above was added to a mixture of 10 g of 8-hydroxyquinoline, 10 g of sodium bicarbonate and 100 ml of methanol. After the reaction mixture was reacted at room temperature for 5 minutes, 5 g of sodium sulfite was added, filtered, washed with 100 ml of water, and concentrated under reduced pressure to give a target compound (19.34 g, 61.0 mmol) as a white solid at 97.0%. Prepared.

¹ H NMR (200 MHz, CDCl ₃ ): δ 8.29 (d, J = 8.8 Hz, 1H), 7.81 (s, 3H), 7.42 (d, J = 8.8 Hz, 1H), 2.76 (s, 3H)

¹³ C NMR (50 MHz, CDCl ₃ + DMSO- _d6 ): δ 158.1, 147.1, 137.9, 134.4, 132.7, 109.4, 106.4, 22.6

MS (EI) 319 (M ⁺ ), 317 (M ⁺ , 100), 315 (M ⁺ ), 289, 208, 128, 102, 64

(Step 2): Synthesis of 7-bromoquinoline-5,8-dione

10.8 g of 5,7-dibromo-8-hydroxyquinoline prepared in step 1 was dissolved in 40 ml of concentrated sulfuric acid. Then 5 ml of nitric acid was added dropwise for 30 minutes at 0 ° C. After the reaction was completed, 300 ml of ice water was added dropwise, extracted with methylene chloride, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (5.81 g, 23.1 mmol) as a light yellow solid in 67.7% of a yield.

¹ H NMR (200 MHz, CDCl ₃ ): δ 8.30 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.56 (s, 3H), 2.80 (s, 3H)

_{^{13 C NMR (50MHz, CDCl 3}} + DMSO -d6): δ181.4, 175.9, 164.8, 145.3, 139.4, 139.1, 134.8, 128.1, 126.4, 23.7

MS (EI) 253 (M ⁺ ), 251 (M ⁺ , 100), 225, 223 197, 195, 172, 144, 116, 89, 74, 63, 53, 39

Anal. Calcd for C ₁₀ H ₆ BrNO ₂ : C, 47.65; H, 2.40; N, 5.56. Found: C, 47.26; H, 2.52; N, 5.51

<Example 15>

Synthesis of 7-piperidinylaminoquinoline-5,8-dione

Using the 7-bromoquinoline-5,8-dione prepared in Example 14 was carried out in the same manner as in Example 2 to prepare a target compound.

mp 157-158 ℃

¹ H NMR (200 MHz, CDCl ₃ ): δ 8.24 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 6.01 (s, 1H), 3.56 (bs, 4H), 2.73 (s, 3H), 1.73 (bs, 6H)

¹³ C NMR (50 MHz, CDCl ₃ ): δ 182.1, 182.0, 162.9, 154.0, 148.0, 133.8, 127.5, 126.9, 108.3, 50.4, 25.7, 24.9, 24.2

MS (EI) 256 (M ⁺ , 100), 227, 213, 189, 161, 145, 117, 101, 84, 41

Anal. Calcd for C ₁₅ H ₁₆ N ₂ O ₂ : C, 70.29; H, 6.29; N, 10.93. Found: C, 70.07; H, 6.61; N, 11.11

As described above, in the preparation method according to the present invention, 7-substituted quinoline-5,8-dione can be produced as a main product by using 6 (7) -haloquinoline-5,8-dione as an intermediate. . In particular, 7-substituted quinoline-5,8-dione derivatives can be prepared in high yield using 6-halo quinoline-5,8-dione as an intermediate.

Claims (7)

7-substituted quinoline-5,8 which is a compound represented by Formula 5 by reacting a compound represented by Formula 2 or Formula 4 with nucleophile R ₅ R ₆ -NH or R ₄ -OH as shown in Scheme 1 below To prepare a dione derivative: <Scheme 1>

Wherein R ₁ , R ₂ and R ₃ are methyl groups or hydrogen; X is halogen and halogen is bromine, chlorine or iodine; R is R ₅ R ₆ -N or R ₄ -O and R is ₄ is selected from a C ₁ to C ₆ chain alkyl group, R ₅ R ₆ -N is a piperidinyl group, methylaziridinyl group, benzyl amine group, n-butyl amine group, cyclohexyl amine group, cyclopentyl amine group , t-butyl amine group, amino group and 4-chloroaniline group; R ₄ and R ₅ R ₆ -N in R ₅ R ₆ -NH or R ₄ -OH are as defined above. The compound of claim 1, wherein R ₁ is a methyl group; R ₂ and R ₃ are hydrogen; X is bromine; R is R ₅ R ₆ -N wherein R ₅ R ₆ -N is a piperidinyl group, methylaziridinyl group, benzyl amine group, n-butyl amine group, cyclohexyl amine group, cyclopentyl amine group, t-butyl A method for preparing a 7-substituted quinoline-5,8-dione derivative, characterized in that it is selected from the group consisting of an amine group, an amino group and a 4-chloroaniline group. As shown in Scheme 2, quinoline-5,8-dione is prepared by reacting a compound represented by Formula 3 with a halogenating reagent in the presence of acetic anhydride (AcOAc) to produce a compound represented by Formula 4. How to: <Scheme 2>

Wherein R ₁ , R ₂ and R ₃ are methyl or hydrogen; X is halogen and halogen is bromine, chlorine or iodine. The quinoline according to claim 3, wherein the halogenating reagent is selected from the group consisting of N-bromosuccinimide, N-chlorosuccinimide, N-iodinesuccinimide, bromine, chlorine and iodine. Method for preparing -5,8-dione. As shown in Scheme 3 below (1) preparing a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 1 with a halogenating reagent (Step 1); And (2) a method of preparing quinoline-5,8-dione, comprising the step (step 2) of preparing a compound represented by Chemical Formula 2 by reacting the compound represented by Chemical Formula 6 with an oxidizing agent: <Scheme 3>

Wherein R ₁ , R ₂ and R ₃ are methyl groups or hydrogen; X is halogen and halogen is bromine, chlorine or iodine; said halogenating reagent is selected from the group consisting of bromine, chlorine or iodine The oxidant is nitric acid. As shown in Scheme 4 below (1) preparing a compound represented by Chemical Formula 4 by reacting the compound represented by Chemical Formula 3 with a halogenating reagent in the presence of acetic anhydride (AcOAc) (Step 1); And (2) a 7-substituted compound comprising reacting a compound represented by Formula 4 with R ₅ R ₆ -NH or R ₄ -OH as a nucleophile to prepare a compound represented by Formula 5 (Step 2) To prepare a quinoline-5,8-dione derivative: <Scheme 4>

Wherein R ₁ , R ₂ and R ₃ are methyl groups or hydrogen; X is halogen and halogen is bromine, chlorine or iodine; R is R ₅ R ₆ -N or R ₄ -O and R is ₄ is selected from a C ₁ to C ₆ chain alkyl group, R ₅ R ₆ -N is a piperidinyl group, methylaziridinyl group, benzyl amine group, n-butyl amine group, cyclohexyl amine group, cyclopentyl amine group , t-butyl amine group, amino group and 4-chloroaniline group; R ₄ R ₆ -NH or R ₄ -OH in R ₄ and R ₅ R ₆ -N are as defined above; The reagent is selected from the group consisting of N-bromosuccinimide, N-chlorosuccinimide, N-iodinesuccinimide, bromine, chlorine and iodine). As shown in Scheme 5 below (1) preparing a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 1 with a halogenating reagent (Step 1); (2) preparing a compound represented by Chemical Formula 2 by reacting the compound represented by Chemical Formula 6 with an oxidizing agent (Step 2); And (3) reacting the compound represented by Chemical Formula 2 with R ₅ R ₆ -NH ₂ or R ₄ -OH, which is a nucleophile, to prepare the compound represented by Chemical Formula 5 (step 3). Process for preparing substituted quinoline-5,8-dione derivatives: Scheme 5

Wherein R ₁ , R ₂ and R ₃ are methyl groups or hydrogen; X is halogen and halogen is bromine, chlorine or iodine; R is R ₅ R ₆ -N or R ₄ -O and R is ₄ is selected from a C ₁ to C ₆ chain alkyl group, R ₅ R ₆ -N is a piperidinyl group, methylaziridinyl group, benzyl amine group, n-butyl amine group, cyclohexyl amine group, cyclopentyl amine group , t-butyl amine group, amino group and 4-chloroaniline group; R ₄ R ₆ -NH or R ₄ -OH in R ₄ and R ₅ R ₆ -N are as defined above; The reagent is selected from the group consisting of bromine, chlorine or iodine; the oxidant is nitric acid).