JPH05194336A - Aminoacrylic acid derivative - Google Patents

Abstract

PURPOSE:To provide an aminoacrylic acid derivative which is a valuable intermediate permitting to produce 8-methoxyquinolone-carboxylic acid useful as a medicine in a high yield and in a high purity without producing toxic by- products. CONSTITUTION:A compound of the formula (R' is lower alkyl), e.g. 3- dimethylamino-2-(2-chloro-4,5-difluoro-3-methoxybenzoyl)acrylic acid ethyl ester. The compound is obtained e.g. by reacting 2-chloro-4,5-difluoro-3-methoxybenzoic acid or its reactive derivative with a 3-dimethylaminoacrylic acid alkyl ester.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an aminoacrylic acid derivative which is a valuable intermediate for producing a novel quinolonecarboxylic acid having a methoxy group at the 8-position, which is useful as a medicine.

[0002]

BACKGROUND OF THE INVENTION A quinolonecarboxylic acid type antibacterial agent having various properties in its antibacterial activity has been actively developed by adding a methoxy group to the quinoline skeleton of a new quinolone type synthetic antibacterial agent. (For example, JP-A-62-252772).

As an intermediate for producing those 8-methoxyquinolonecarboxylic acids, there is disclosed in JP-A-62-2527.
Compounds of the general formula (2) described in Japanese Patent No. 72 (2) and compounds of general formula (3) described in JP-A-63-316757. (3) can be mentioned, but both are not satisfactory in yield at the time of ring closure, and cannot be said to be an industrial reaction because harmful hydrogen fluoride is by-produced at the time of ring closure.

[0004]

As a result of intensive studies to solve the above problems, the present inventors have found that the aminoacrylic acid derivative, which is the compound of the present invention, has a value for producing 8-methoxyquinolonecarboxylic acid. They found that it was an intermediate, and completed the invention. By using the compound of the present invention, 8-methoxyquinolonecarboxylic acid can be produced in high yield and high purity without generating harmful by-products.

The compounds of the present invention are, for example, 2-chloro-
It can be produced by reacting 4,5-difluoro-3-methoxybenzoic acid or its reactive derivative with 3-dimethylaminoacrylic acid alkyl ester.

This reaction is carried out in a solvent such as methylene chloride, chloroform, ether, tetrahydrofuran, etc.
Preference is given to working between 0 ° C. and the boiling point of the solvent. 2-
As a reactive derivative of chloro-4,5-difluoro-3-methoxybenzoic acid, an acid halogen compound, particularly an acid chloride is preferable.

[0007]

EXAMPLES The present invention will be described in more detail by showing production examples according to the present invention as examples.

Example 1 3-Dimethylamino-2- (2-chloro-4,5-difluoro-3-methoxybenzoyl) acrylic acid ethyl ester

2-Chloro-4,5-difluoro-3-methoxybenzoyl chloride (28.1 g) (compound of Reference Example 5) was dissolved in 138 ml of tetrahydrofuran and cooled to 5 ° C. or lower. Ethyl 3-dimethylaminoacrylate was added to this solution. 18.0 g and triethylamine 13.2 g at 5 ° C
Dropped below.

After stirring at room temperature for 30 minutes, the mixture was heated under reflux for 2 hours. Cool, add 280 ml of water, and add methylene chloride 28
It was extracted with 0 ml × 3 times. The extract was washed with water and dried, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (benzene: ethyl acetate = 5: 2) to obtain 38.4 g of the desired product. Mass (m / e): 349 (M ⁺ +2)

The starting material, 2-chloro-4,5-difluoro-3-methoxybenzoyl chloride, is 2,3,4-which is widely used as a raw material for quinolonecarboxylic acid.
It can be synthesized from trifluoroaniline in 5 steps.

Reference Example 1 6-Bromo-2,3,4-trifluoroaniline

2,3,4-trifluoroaniline 147
g in 700 ml of glacial acetic acid and bromine 160 while stirring
A solution of g in 160 ml of acetic acid was added dropwise at 40 ° C. for 1 hour. The reaction solution was stirred at room temperature for 1 hour, poured into 2 L of ice water, and the precipitated crystals were collected by filtration. This was dissolved in 500 ml of methylene chloride and water,
It was washed successively with aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated to give the target product 21 as light brown crystals.
8.1 g was obtained.

Melting point 58-59 ° C. NMR (δ in CDCL ₃ ): 7.10 (ddd,
J = 2.6, 7.4, 9.2 Hz)

Elemental analysis value (%): Calculated value as C ₆ H ₃ BrF ₃ N: C; 31.98, H; 1.34, N; 6.20 Actual value: C; 31.85, H; 1 .38, N; 6.33

Reference Example 2 1-Bromo-2-chloro-3,4,5-trifluorobenzene

213 g of 6-bromo-2,3,4-trifluoroaniline and 152 g of anhydrous cupric chloride were added to 800 ml of anhydrous acetonitrile and stirred, and 116 g of t-butyl nitrite was added thereto at 45 to 47 ° C. at 30 ° C. Dropped in minutes. After stirring for 30 minutes at room temperature, the reaction solution was poured into a dilute aqueous hydrochloric acid solution and the precipitated oily substance was extracted with petroleum ether. The organic layer was washed successively with dilute hydrochloric acid, water and an aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by distillation to obtain 150.9 g of the desired product.

Boiling point 82-83 ° C./30 mmHg NMR (δ in CDCl ₃ ): 7.34 (ddd,
J = 2.2, 7.0, 9.2 Hz)

Reference Example 3 3-Bromo-2-chloro-5,6-difluoroanisole

170.1 g of 1-bromo-2-chloro-3,4,5-trifluorobenzene was added to 1 L of anhydrous methanol solution of sodium methoxide, and the precipitated oily matter was extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated, and the residue was purified by distillation to obtain 142.2 g of the desired product.

Boiling point 95-108 ° C./13 mmHg NMR (δ in CDCl ₃ ): 4.02 (3H,
d, J = 1.8 Hz) 7.24 (1H, J = 7.4, 9.2 Hz)

Reference Example 4 2-chloro-4,5-difluoro-3-methoxybenzoic acid

212 ml of tetrahydrofuran was added to 10.20 g of magnesium. 3-Bromo-2-chloro-5,6-difluoroanisole 10 with vigorous stirring
A small amount of 5.9 g of a 106 ml solution of tetrahydrofuran was added dropwise, and the reaction solution was heated to 30 ° C. When the reaction started, the remaining solution was added dropwise at 30 to 35 ° C., the mixture was stirred at the same temperature for 1 hr, and then ice-cooled. Add 1 kg of dry ice to the reaction mixture and stir further. When the dry ice had disappeared, the reaction solution was poured into 1500 ml of water, 85 ml of 6N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated to obtain 89.37 g of the desired product.

Melting point 122-127 ° C. NMR (δ in CDCl ₃ ): 4.03 (3H,
d, J = 1.6 Hz) 7.56 (1H, dd, J = 8.0, 10.0 Hz),
11.46 (1H, s)

Reference Example 5 2-Chloro-4,5-difluoro-3-methoxybenzoyl chloride

150 ml of toluene and 21 ml of thionyl chloride were added to 50.1 g of 2-chloro-4,5-difluoro-3-methoxybenzoic acid, and the mixture was stirred at 80 ° C. for 1 hour and 30 minutes. After distilling off toluene and excess thionyl chloride, the residue was distilled under reduced pressure to obtain 47.39 g of the desired product as a yellow oil. Boiling point 96 ° C / 2mmHg

The aminoacrylic acid derivative produced by the present invention can be converted into industrially useful 8-methoxyquinolonecarboxylic acid by the following steps.

Reference Example 6 3-Cyclopropylamino-2- (2-chloro-4,5)
-Difluoro-3-methoxybenzoyl acrylic acid ethyl ester

3-dimethylamino-2- (2-chloro-
4,5-Difluoro-3-methoxybenzoyl) acrylic acid ethyl ester 31.4 g (Example 1) was dissolved in methylene chloride and cyclopropylamine 6.43 was cooled.
g was added dropwise at 10 ° C or lower. After stirring at room temperature for 1 hour, the reaction solution was washed with water and dried, and then the solvent was distilled off. 60% on the residue
Crystallization is performed by adding 63 ml of ethanol water, and the target product 2
3.5 g was obtained.

Melting point 89-91 ° C. NMR (δ in CDCl ₃ ): 0.80-1.08
(7H, m), 2.84-3.06 (1H, m), 3.
99 (3H, d), 4.00 (2H, q), 6.66-
6.85 (1H, m), 8.26 (1H, dd), 1
1.04 (1H, brs)

Reference Example 7 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid ethyl ester

A) 3-Cyclopropylamino-2- (2
-Chloro-4,5-difluoro-3-methoxybenzoylacrylic acid ethyl ester 43.0 g was added to dioxane 2
It was dissolved in 60 ml and heated to 50 ° C. 6.3 g of 55% sodium hydride was added at 50-60 ° C over 30 minutes, and the mixture was stirred at the same temperature for 10 minutes and then cooled. The reaction solution was poured into 2 L of ice water, and the precipitated crystals were collected by filtration to obtain 38.1 g of the desired product.

Melting point 177 to 178 ° C. NMR (δ in CDCl ₃ ): 1.07-1.26
(4H, m), 1.40 (3H, t), 3.86-4.
00 (1H, m), 4.08 (3H, d) 4.38 (2
H, q), 8.02 (1H, dd), 8.59 (1H,
S)

B) 3-Cyclopropylamino-2- (2
3.6 g of -chloro-4,5-difluoro-3-methoxybenzoylacrylic acid ethyl ester and 2.08 g of anhydrous calcium carbonate were dissolved in 18.0 ml of dimethylformamide, and the mixture was heated under reflux for 3 hours with stirring. Cool the reaction,
The reaction solution was poured into 360 ml of ice water, and the precipitated crystals were collected by filtration to obtain 2.59 g of the desired product. The instrument spectrum was in agreement with that obtained in A).

C) Dimethylacetamide (DMAC) 1
4.15 g of anhydrous potassium carbonate was added to 0 ml, and 1 with stirring.
The temperature was raised to 20 ° C. 3-Cyclopropylamino-2- (2-chloro-4,5) dissolved in 10 ml of DMAC at the same temperature
-Difluoro-3-methoxybenzoyl acrylic acid ethyl ester 3.6g was poured, and it was made to react at 115-125 degreeC for 1 hour 30 minutes. The reaction solution was cooled, poured into 360 ml of ice water, and the precipitated crystals were collected by filtration to obtain 2.73 g of the desired product. The instrument spectrum was in agreement with that obtained in A).

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[Procedure amendment]

[Submission date] February 20, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0010

[Correction method] Change

[Correction content]

After stirring at room temperature for 30 minutes, the mixture was heated under reflux for 2 hours. Cool, add 280 ml of water, and add methylene chloride 2
It was extracted with 80 ml × 3 times. The extract was washed with water and dried, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (benzene: ethyl acetate = 5: 2) to obtain 38.4 g of the desired product. Melting point 70 to 71.5 ° C. Elemental analysis value (%) As C ₁₅ H ₁₆ ClF ₂ NO _4. NMR spectrum (CDCl ₃ , δPPM): 0.9
_{7 (t, 3H, J =} 7Hz, CH 2 C H 3), 3.18
_{(Bs, 6H, N (CH} 3) 2), 3.98 (q, 2
_{H, J = 7Hz, C H} 2 CH 3), 4.00 (d, 3
H, J = 2 Hz, OC H ₃ ), 6.99 (dd, 1H,
J = 8, 10 Hz, aromatic proton), 7.85 (s,
1H, olefin proton) IR spectrum (KBr, cm ^-1 ): 3036, 29
88, 1690, 1640 Mass spectrum (m / e): 349 (M ⁺ +2)

Claims (1)

[Claims] 1. The general formula (1) (1) An aminoacrylic acid derivative represented by the formula (wherein R ¹ represents a lower alkyl group).