KR930011037B1 - Process for preparation of carboxy quinoline derivatives - Google Patents

Abstract

Quinolone carboxylic acid derivatives of formula (I) are prepared by (a) reacting 2,4-dichloro-5-fluorobenzoylacetone with triethylorthoformate in the presence of anhydrous acetic acid to obtain ethoxy butenone compound, (b) refluxing with cyclopropylamine to obtain 6-fluoro-7-chloro-1-cyclopropyl1,4- dihydro-3-acetyl-4-oxoquinoline of formula (II), and (c) reacting (II) with piperazine. In the formula (I), R=H, C1-4 alkyl; R'=H, C1-4 alkyl, alkoxycarbonyl, or C1-4 alkylester.

Description

Method for preparing quinoline carboxylic acid derivative

The present invention relates to a quinoline derivative represented by the following general formula (I) and a method for producing a salt or a hydrate thereof.

In the above formula, R is hydrogen or an alkyl group having 1 to 4 carbon atoms, and R 'is hydrogen, lower alkyl having 1 to 4 carbon atoms, alkoxycarbonyl, or alkyl ester having 1 to 4 carbon atoms. The structural formula (I) is a compound that shows much superior activity to all gram-positive bacteria, gram-negative bacteria, and Pseudomonas aeruginosa than conventional quinoline derivatives such as naridic acid or pipemidic acid. It is a compound widely used throughout dermatology and otolaryngology.

The compound of formula (I) is a known compound and its preparation method is described in detail in European Patent No. 78, 362, Japanese Patent Application Laid-Open No. 58-74,667, German Patent No. 3, 142,854, and the like. Looking at these known conventional manufacturing methods are as follows.

Diethylmalonate of formulas (II) and (III) is acylated in the presence of magnesium alkoxide to prepare a compound of formula (IV) which is an acyl maronate compound.

The compound of formula (IV) was partially hydrolyzed in an aqueous solution containing paratoluene sulfonic acid, followed by decarbonation to obtain a compound of formula (V), and then reacted with triethyl ortho formate and acetic anhydride to obtain a compound of formula (VI). Obtain ethyl-2- (2 ', 4'-dichloro-5'-fluoro banjoyl) -3-ethoxyacrylic acid. Compound (VI) is reacted with cyclofurophylamine in a solvent of methylene chloride, alcohol, chloroform, cyclo hexane or toluene to obtain compound (VII), and dioxane, dimethyl sulfoxide, N in a temperature range of 80 to 180 ° C. Methylpyrrolidone, N, N-dimethylformamide or the like is used as a diluent and sodium hydride as an acid binder to obtain a structural formula. This compound of the objective substance (I) was condensed with pyreazine. Meanwhile, the method for preparing the compound 2,4-dichloro-5-fluoro benzoyl chloride used as a starting material in the above (Scheme I) is as follows (Scheme II).

That is, diazotization, fluorination, and chlorination were carried out using 2,4-dichloro-5-methyl aniline as a starting material to prepare a compound of formula II, and hydrolyzed with 95% sulfuric acid to obtain a compound III. This is obtained by using thionyl chloride to obtain a compound of formula II.

Thus, to obtain the target compound (I) with 2,4-dichloro-5-methylaniline as the first starting material, 12 complex steps and special equipment and equipment for fluorination are required. Due to low overall yield, it has a disadvantage of low economic feasibility.

The present inventors started from the general formula (A) compound which can be manufactured at low cost without going through such a complicated process, and can produce the target compound (I) in only 3 steps and 5 steps. The process was developed to complete the present invention.

The present invention is described in the following scheme (Reaction Scheme III).

X 'in the above formula is halogen, in particular fluorine, chlorine or C ₁ -C ₄ alkylsulfonyl or C ₁ -C ₄ alkylsulfonyloxy group and X ² is halogen in particular fluorine, chlorine or nitro group.

(A) The compound (when X ¹ , X ² is chlorine) is known from Zh ohschch khim 32.3131 (1962) and the preparation method (when X ¹ is fluorine and X ² is chlorine) JP 1045332 A, JP 2017147 A, JP 2131453 A describes the preparation method in detail.

(Wherein X ¹ and X ² are as described above).

Compound (B) is a novel substance, the ketone compound (A), which is a starting material, and acetic anhydride are mixed in a 1: 2 molar ratio and rapidly saturated with boron trifluoride at a temperature of 10 to 20 ° C. for 20 minutes to 2 hours. Pass slowly for 2 hours and treat with dilute sodium acetate solution to obtain compound (B) in high yield of 80% or more.

(B) The preparation method of the compound is

(B) is reacted with acetic anhydride and triethyl formate at a temperature of 50 to 150 ° C, preferably 120 to 140 ° C for 1 to 3 hours. Compound (C) is obtained in quantitative yield. The ethoxy buteneone (C) compound thus obtained was dissolved in methylene chloride, methanol, ethanol, dioxane or toluene, preferably in ethanol or dioxane solvent, and cyclopropyl amine was added at room temperature and stirred for 30 minutes to 1 hour. Sodium hydride, potassium potassium bicarbonate, potassium potassium carbonate and t-butyl potassium potassium butoxide are preferably added with an acid binder. Sodium hydride is preferably added, stirred at room temperature for 30 minutes to 1 hour, and then heated to reflux for 1 to 3 hours.

After cooling, about 2/3 of the solvent was removed, and water was added to the mixture, followed by stirring to quantitatively produce the cyclic cyclic compound (E).

The preparation method of the target compound (I) can be prepared by two methods as follows.

First, the cyclized compound (E) is added with 1 to 4 equivalents of a pyrazine derivative in an organic solvent using a catalyst, and then 4 to 48 hours at a temperature of 20 to 160 ° C, preferably 40 to 100 ° C, preferably 4 After reacting for 18 hours, the solvent is removed under reduced pressure and crystallized by addition of water. As the organic solvent, lower alcohols such as tetrahydrofuran, pyridine, quinoline, dioxane, isoprophylethers, ethanol, furopanol, butanol or acetonitrile, dimethylformamide and dimethyl sulfoxide, preferably pyridine or dioxane Tetraphenyl phosphonium bromide and iodine, benzyltriethyl ammonium bromide and iodine, chromium hexacarbonyl or transition metal salts such as CuCl, CuCl ₂ , CoCl, NiCl, or Cu, Ni, Co, etc. The amount used may be 10 to 150%, preferably 20 to 100%. The reaction may also be carried out using triethyl amine, pyridine, quinoline, etc. as an acid binder without using a catalyst. The dried material thus obtained is added to the above-mentioned organic solvent again and 1 to 2 equivalents of iodine is added, and then 20 to 160 ° C, preferably 50 to 100 ° C for 20 minutes to 5 hours, preferably 30 minutes to 4 hours. After the reaction was conducted for a period of time, the solvent was removed under reduced pressure, a diluted alkaline aqueous solution was added, stirred at room temperature for 100 minutes to 2 hours, cooled, and the pH was adjusted to 3-7, preferably 3-4 with acetic acid, thereby adjusting the target compound (I). Get

Second, the converted (E) compound was added to the above-mentioned organic solvent, iodine was added 1-2 times equivalent, and reacted under the same conditions as the first method, crystallized with water, filtered and dried. Then, piperazine was added to 1 After adding -4 equivalents and reacting under the same conditions as above, the target compound (I) is prepared by adjusting the pH to 3-4 times. In this reaction, the intermediate (E ') can be used directly in the next reaction with or without separation. It is preferred to react without separation.

The present invention will be described with reference to Examples, but the following Examples do not limit the present invention.

Example 1

Method for preparing 2.4-dichloro-5-fluoro benzoyl acetone (B) 18 g (86.94 mmol) of 2.4-dichloro-5-fluoro acetophenone (A) was added to 21 ml of acetic anhydride and maintained at 10 ° C. to 15 ° C. The trifluoride gas is rapidly saturated for 20 minutes. Slowly inject boron trifluoride gas over 2 hours with vigorous stirring with a mechanical stirrer. After the reaction was completed, 280 ml of 13% aqueous acetic acid aqueous solution was added to the reaction solution and refluxed for 1 hour. After cooling, the mixture was extracted with 100 ml of chloroform, washed three times with 30 ml of saturated aqueous sodium bicarbonate solution, twice with 30 ml of water, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. 50 ml of n-hexane is added to the oil phase, followed by stirring to form crystals. Filtration and drying gave 19 g (87.8%) of the title compound (B).

Melting point = 69 ° C

nmr (CDCl ₃ ) ppm: 2.0 (s, 3H), 2.3-2.6 (m, 1H), 6.0 (s, 1H), 7.1-7.3 (m, 1H), 7.4-7.8 (m, 1H).

Example 2

Method for preparing 2-chloro-4,5-difluoro benzoyl acetone (B ′) 16.6 g (86.94 mmol) of 2-chloro-4,5-difluoro acetophenone was added to the compound (B) of Example 1 In the same manner as in the preparation of 19.4g (96%) of the title compound as an oil was obtained. The oily product is used in the next reaction without any further stagnation.

nmr (CDCl ₃ ) ppm: 2.0 (s, 3H), 2.3-2.5 (m, 1H), 6.0 (s, 1H), 7.1-7.3 (m, 1H), 7.4-7.8 (m, 1H)

Example 3

[Method for preparing 3- (2 ', 4'-dichloro-5'-fluoro benzoyl) -4-ethoxy-3-buten-2-one (C)]

Ethyl acetate produced during the reaction by adding 10.7 ml of 2-4-dichloro-5-fluoro benzoyl acetone (B) and 10.7 ml of triethylorthoformate and 21.2 ml of acetic anhydride and stirring at 130 DEG C for 2 hours. Remove it.

After the reaction is complete, it is cooled and the remaining solvent is removed by reduced pressure. Wash out three times with 80 ml of toluene. The oily product is used for the next reaction without further purification.

Yield: 20.05 g (99.3%)

Example 4

[Method for preparing 3- (2'-chloro-4 ', 5'-difluoro benzoyl) -4-ethoxy-3-buten-2-one (C')]

15.4 g (66.25 mmol) of 2-chloro-4,5-difluorobenzoyl acetone (B), 10.7 ml of triethylorthoformate, and 21.2 ml of acetic anhydride were added and treated in the same manner as in (C). 18.75 g (98%) of the title compound are obtained. The oily product is used for the next reaction without further purification.

Example 5

[Method for preparing 3- (2 ', 4'-dichloro-5'-fluoro benzoyl) -4-cyclofurophyl amino-3-buten-2-one (D)]

20.05 g (65.71 mmol) of 2- (2 ', 4'-dichloro-5'-fluoro benzoyl) -4-ethoxy-3-buten-2-one (C) in oil phase, 200 ml of methylene chloride, cyclofuro Add 8 ml (0.115 mol) of filamine and stir at room temperature for 1 hour.

After the reaction was completed, the solvent was filtered off and dried under reduced pressure, and 450 ml of a mixed solvent of n-hexane-petroleum ethyl (4: 1) was added to the oily substance, stirred at room temperature for 30 minutes, and then filtered and dried to obtain 17 g (81.8%) of the title compound. Get

Melting Point: 118 ℃

nmr (CDCl ₃ ) ppm: 0.6 to 1.0 (m, 4H), 2.2 (s, 3H), 2, 6 to 3.0 (m, 1H), 7.0 to 7.4 (m, 2H), 7.4 (s, 1H), 11.1-11.5 (bs, 1 H).

Example 6

[Method for preparing 3- (2'-chloro-4 ', 5'-difluoro benzoyl) -4-cyclofurophyllamino-3-buten-2-one (D')]

에 가해 용해하고 시클로푸로필 아민 42ml(0.61몰)을 실온을 유지하면서 서서히 가해준다. 이 온도에서 1야 교반후 농축하여 디옥산을 제거하고 오일상의 물질에 n-헥산-석유에텔(4:1) 혼합용액 3.4ℓ을 가한 후 실온에서 301분간 교반후 여과 건조하여 상기 표제 화합물 120g(80%)을 얻는다.144.8 g (0.5 mol) of 3- (2'-chloro-4 ', 5'-difluoro benzoyl) -4-ethoxy-3-buten-2-one to 1.4-dioxane 1

It is dissolved in the solution, and 42 ml (0.61 mole) of cyclofurophyl amine is added slowly while maintaining the room temperature. After stirring overnight at this temperature, the solution was concentrated to remove dioxane, and 3.4 liters of n-hexane-petroleum ether (4: 1) mixed solution was added to the oily substance, stirred at room temperature for 301 minutes, and then filtered and dried to obtain 120 g of the title compound. 80%).

Melting Point: 115 ℃

nmr (CDCl ₃ ) ppm: 0.6 to 1.0 (m, 4H), 2.2 (s, 3H), 2,6 to 3.0 (m, 1H), 7.1 to 7.4 (m, 2H), 7.4 (s, 1H), 11.1-11.5 (bs, 1 H).

Example 7

[Method for preparing 6-fluoro-7-chloro-1-cyclopropyl-1.4-dihydro-3-acetyl-4-oxoquinoline (E)]

15 g (47.44 mmol) 2- (2 ', 4'-dichloro-5'-fluoro benzoyl) -3-cyclofurophyl amino-3-buten-2-one (D), 143 ml dioxane, 55-60 Add 2.3 g (52.4 mmol) of% sodium hydride and stir at room temperature for 30 minutes.

Heat slowly to reflux for 2 hours. After completion of the reaction, 2/3 of the dioxane solvent is removed by distillation under reduced pressure. 140 ml of water was added to the resulting suspension, stirred at room temperature for 30 minutes, filtered and washed with water. After thorough filtration, the suspension was stirred in 250 ml of n-hexane-petroleum ether (4: 1), followed by filtration and drying. 11.8 g 988.9% of the title compound) is obtained.

Melting Point: 160 ℃

nmr (CDCl ₃ ) ppm: 1.0 to 1.4 (m, 4H), 2.5 (s, 3H), 3.20 to 3.5 (m, 1H), 7.8 to 8.20 (m, 2H), 8.4 (s, 1H).

Example 8

[Method for preparing 6,7-diluoro-1-cyclofurophyll-1.4-dihydro-3-acetyl-4-oxoquinoline (E ')]

1.5 l of 3- (2'-chloro-4 ', 5'-diluoro benzoyl) -4-cyclofurophyllamino-3-buten-2-one (1.5 mol) in 1,4-dioxane Is dissolved in and 24.7 g (0.57 mol) of 55-60% NaH is added. After stirring at room temperature for 30 minutes, the mixture was slowly warmed and maintained at 90-95 ° C. for 1 hour. After cooling, the solvent was concentrated to 1/3 by reduced pressure. 300 ml of water is added to the residue, and the resulting crystals are filtered and dried. Purify with 300 ml of n-hexane-petroleum (4: 1) solution to afford 105 g (80%) of the title compound.

Melting Point: 170 ℃

nmr (CDCl ₃ ) ppm: 1.0 to 1.4 (m, 4H), 2.5 (s, 3H), 3.2 to 3.5 (m, 1H), 7.8 to 8.2 (m, 2H), 8.4 (s, 1H).

Example 9

[Method for preparing 6-fluoro-7- (piperazin-1-yl) -1-cyclofurophyll-1,4-dihydro-3-acetyl-4-oxoquinoline (F)]

1.39 g (4.97 mmol) of 6-fluoro-7-chloro-1-cyclofurophil-1.4-dihydro-3-acetyl-4-oxoquinoline (E) was added to 12 ml of pyridine and 0.52 g (6.04 mmol) of piperazine. Add 0.06 g of iodine and 0.06 g of benzyltriethylammonium bromide. Warm to reflux for 18 hours. After cooling, pyridine was removed by depressurization, and 10 ml of water was added thereto, followed by stirring to form crystals. The resulting crystals are filtered off, washed with water and dried. Recrystallize from chloroform if necessary to yield 1.15 g (70%) of the title compound.

Melting Point: 203 ℃

nmr (TFA-d) ppm: 1.2 to 1.8 (m, 4H), 2.8 (s, 3H), 3.5 to 4.2 (d, m, 10H), 7.8 to 8.4 (m, 2H), 8.6 (s, 1H) .

Example 10

[Method for preparing 6-fluoro-7- (piperazin-1-yl) -1-cyclofurophyll-1,4-dihydro-3-acetyl-4-oxoquinoline (F ')]

65 g (0.25 mol) of 6,7-difluoro-1-cyclofurophyll-1.4-dihydro-3-acetyl-4-oxoquinoline, 130 g of piperazine (mol) pyridine, 65 ml of triethylamine, dimethyl sulfoxide 200 ml was added sequentially and mixed, followed by reaction at 45 ° C. to 50 ° C. for 3 hours. After cooling, pyridine and triethyl amine were removed by concentration under reduced pressure, 400 ml of water was added to the residue, the mixture was stirred, filtered, and dried and purified by ether to give 57.6 g (70%) of the title compound.

Melting Point: 203 ℃

nmr (TFA-d) ppm: 1.2 to 1.8 (m, 4H), 2.8 (s, 3H), 3.5 to 4.2 (d, m, 10H), 7.8 to 8.4 (m, 2H), 8.6 (s, 1H) .

Example 11

[Method for preparing 6-Fluoro-7- (piperazin-1-yl) -1-cyclofurophyll-1.4-dihydro-4-oxo-3-quinoline carboxylic acid (I)]

6-fluoro-7- (piperazin-1-yl) -1-cyclofurophyll-1.4-dihydro-3-acetyl-4-oxoquinoline9.9g (0.03 mol), 8.9g of iodine and 50ml of pyridine Stir for 4-5 hours while maintaining 55-60 ° C. Cooling was added 1.7 g of Nal at room temperature, stirred for 30 minutes, and concentrated under reduced pressure to remove pyridine. 500 ml of 2% aqueous NaOH solution was added to the residue, and the mixture was refluxed for 1 hour. Then, 0.5 g of activated carbon was added thereto, stirred for 5 minutes, and filtered while heated. After cooling, the filtrate is adjusted to pH 4 with acetic acid to form crystals. The resulting crystals are collected by filtration, drying. The crude product obtained by concentrating the filtrate was further purified by column chromatography with dichloromethane: methanol: acetonitrile: acetic acid (4: 4: 1: 2) solution and combined with the crystals obtained firstly. : Ammonia water: Acetonitrile (2: 2: 1: 0.5) solution was added to 0.791 and warmed to reflux for 1 hour. After cooling, 15 ml of water was added to the residue, followed by stirring, filtration and drying to obtain 8.45 (85%) of the title compound.

Melting Point: 255 ℃ ~ 257 ℃

Example 12

[Method for preparing 6-Fluoro-7- (piperazin-1-yl) -1-cyclofurophyll-1.4-dihydro-4-oxo-3-quinoline carboxylic acid (I)]

8.4 g (0.03 mol) of 6-fluoro-7-chloro-1-cyclofurophyl-1.4-dihydro-3-acetyl-4-oxoquinoline was dissolved in 25 ml of pyridine, and 7.6 g (0.03 mol) of iodine was added thereto. It stirs for 30 minutes at ° C-100 ° C. After cooling, pyridine was removed by reduced pressure, 50 ml of water was added to the residue, and the resulting crystals were filtered and dried. The crystals were again dissolved in 40 ml of pyridine, 0.4 g of tetraphenylphosphonium bromide, 0.3 g of iodine, and 13.5 g of piperadine were added, followed by warming and stirring under reflux for 2 hours. After cooling, the mixture was distilled under reduced pressure under high vibration to completely remove pyridine and excess piperadine. Then, 500 ml of a 2% aqueous NaOH solution was added to the residue, which was then heated to reflux for 1 hour. Lastly, 0.7 g of activated carbon was added and refluxed for 5 minutes, followed by filtration on hot water, cooling the filtrate and adjusting to pH 4 with acetic acid to form crystals.

The resulting crystals are collected by filtration drying. The Example was then treated in the same manner as in Example 11 to yield 8 g (80%) of the title compound.

Example 13

[Preparation method of 6-fluoro-7- (piperazin-1-yl) -1-cyclofurophyll-1,4-dihydro-4-oxo-3-quinoline carboxylic acid]

7.9 g (0.03 mol) of 6,7-difluoro-1-cyclofurophyll-1,4-dihydro-3-acetyl-4-oxoquinoline was dissolved in pyridine, and 7.6 g (0.03 mol) of iodine was added to give 98. It stirs for 30 minutes at ° C-100 ° C. After cooling, pyridine was removed by reduced pressure, 50 ml of water was added to the residue, and the resulting crystals were filtered and dried. The crystals obtained above were dissolved again in 40 ml of pyridine, 0.4 g of tetraphenyl phosphonium boride and 0.3 g of piperazine were added thereto, followed by reaction at 45-50 ° C. for 3 hours. Thereafter, 7 g (70%) of the title compound was obtained under the same conditions as in Example 12.

Example 14

[Preparation method of 6-fluoro-7- (piperazin-1-yl) -1-cyclofurophyll-1,4-dihydro-4-oxo-3-quinoline carboxylic acid]

8.4 g (0.03 mol) of 6-fluoro-7-chloro-1-cyclofurophyll-1,4-dihydro-3-acetyl-4-oxoquinoline was dissolved in 25 ml of pyridine and 7.6 g (0.03 mol) of iodine Add and stir at 98 ° C-100 ° C for 30 minutes. After cooling, pyridine was removed by reduced pressure, 50 ml of water was added to the residue, and the resulting crystals were filtered and dried. The crystals obtained above were dissolved in 58 ml of pyridine, 0.39 g of tetraphenyl phosphonium bromide, 0.35 g of iodine, and 21.63 g of piperazine hexahydrate were added, followed by heating and refluxing for 6 hours. After cooling, the mixture was distilled under reduced pressure under high vacuum to completely remove pyridine and excess piperazine. Then, 315 ml of a 2% aqueous NaOH solution was added to the residue, which was then heated to reflux for 1 hour. Finally, 0.68 g of activated carbon was added and refluxed for 5 minutes, followed by filtration over hot water, cooling the filtrate, and adjusting the pH to 4 with acetic acid to form crystals. The resulting crystals are collected by filtration drying. The subsequent procedure was followed the same procedure as in Example 11 to give 8.3 g (83%) of the title compound.

Melting Point: 255 ℃ -257 ℃

nmr (TFA-d) ppm: 1.2 to 1.8 (m, 4H), 3.4-4.2 (m, 10H) 7.8-8.0 (d, 1H), 8.0-8.2 (d, 1H) 9.2 (s, 1H).

Claims (1)

In one reactor, the compound of the following formula (E) is treated with an excess of pyridine and 1-2 times equivalent of iodine to form an acylpyridium iodine compound (F), followed by reaction with 1-4 times equivalent of anhydrous piperazine. To prepare a compound of formula (I) by treatment with a dilute aqueous alkali solution or by reacting with piperazine hydrate.

In the formula, X 'represents a halogen atom.