JPH04297467A - 3-amino-2-benzoylacrylic acid derivative, production thereof and new production of quinolonecarboxylic acid derivative using the same derivative - Google Patents

Abstract

PURPOSE:To obtain a compound useful as an antimicrobial agent under a mild condition in a short reaction time in high yield, safely and industrially by using a 3-amino-2-benzoylacrylic acid derivative as an intermediate. CONSTITUTION:A compound shown by formula I (R<1> and R<2> are H, alkyl, cycloalkyl, etc.; R<3> is H, alkyl, etc. ; R<4> and R<5> are alkyl; R<6> is H or alkyl; X is H, halogen, etc.; n is 1-3). The compound is obtained by reacting a compound shown by formula II with an aminoacrylic acid derivative shown by formula III. The compound shown by formula I is reacted with an amine derivative shown by the formula H2NR<7> (R<7> Is alkyl or cycloalkyl), then subjected to ring formation and optionally deprotected to give a compound shown by formula IV.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention provides a general formula with excellent antibacterial action.

[In the formula, R1 and R2 are the same or different and represent hydrogen, alkyl, cycloalkyl, aralkyl, acyl or alkoxycarbonyl, or R1 and R2 combine with each other to form a heterocycle together with the adjacent nitrogen atom. R3 represents hydrogen, alkyl, aralkyl, or an ester residue that can be hydrolyzed in vivo, R6 represents hydrogen or alkyl, and R7 represents alkyl, cycloalkyl, haloalkyl, alkenyl, mono- or dialkylamino. , phenyl, or phenyl having 1 to 3 of halogen, alkyl, alkoxy, hydroxyl, nitro, or amino as a substituent, X represents hydrogen, halogen, or alkyl, and n represents an integer of 1 to 3. ] A novel method for producing quinolone carboxylic acid derivatives represented by the general formula and its synthetic intermediates

embedded image [In the formula, R4 and R5 represent alkyl, and the other symbols have the same meanings as above. 3-amino-2-benzoyl acrylic acid derivative represented by ].

0002

[Prior Art] JP-A-2-138278 discloses, for example, the acid chlorination of 4-[2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholino]-2,3,5-trifluorobenzoic acid. 4-[2-(N-
Ethoxycarbonyl-N-methylaminomethyl)morpholino]-2,3,5-trifluorobenzoylacetic acid ethyl ester was obtained, treated with dimethylformamide dimethyl acetal, and further treated with cyclopropylamine to obtain 2-[4-[2 -(N-ethoxycarbonyl-N-methylaminomethyl)morpholino]-2,3,5-trifluorobenzoyl]-3-cyclopropylaminoacrylic acid ethyl ester and then cyclized to 6,8-difluoro -1,4-dihydro-7-[2-
(N-ethoxycarbonyl-N-methylaminomethyl)
A method for making morpholino]-4-oxo-3-quinolinecarboxylic acid ethyl ester is described.

0003

[Problems to be Solved by the Invention] However, when the method of JP-A-2-138278 mentioned above is used industrially, it has disadvantages such as requiring time for the reaction and having a long reaction process. Ta.

0004

[Means for Solving the Problems] As a result of extensive research into the industrial production method of the quinolone carboxylic acid derivative of the general formula (V), the present inventors found that the 3-amino-
The present invention has been completed by discovering that a new production method using a 2-benzoyl acrylic acid derivative can safely produce the target substance in a short period of time and in high yield under mild conditions.

Specifically, the present invention provides (1) a compound of the general formula (V) useful as a synthetic intermediate for a quinolone carboxylic acid derivative represented by the general formula (V);

embedded image [In the formula, each symbol has the same meaning as above. ] A 3-amino-2-benzoyl acrylic acid derivative represented by

0
(2) General formula

embedded image [In the formula, each symbol has the same meaning as above. ] or its reactive derivative, the general formula

embedded image [In the formula, each symbol has the same meaning as above. ] A method for producing a 3-amino-2-benzoyl acrylic acid derivative represented by general formula (I), which comprises reacting an amino acrylic acid derivative represented by

(3) 3- represented by general formula (I)
The amino-2-benzoyl acrylic acid derivative has the general formula

[
[In the formula, R7 is alkyl, cycloalkyl, haloalkyl, alkenyl, mono- or dialkylamino, phenyl, or a phenyl group having 1 to 3 of halogen, alkyl, alkoxy, hydroxyl, nitro, or amino as a substitution method. reacting an amine derivative represented by]
A method for producing a quinolone carboxylic acid derivative represented by the general formula (V), which is then cyclized and optionally subjected to a deprotecting group reaction.

(4) A compound represented by general formula (II) or a reactive derivative thereof is reacted with an aminoacrylic acid derivative represented by general formula (III) to form a 3-amino-acrylic acid derivative represented by general formula (I). A 2-benzoyl acrylic acid derivative is obtained, further reacted with an amine derivative represented by the general formula (IV), then cyclized, and optionally subjected to a deprotection reaction.
) The present invention relates to a method for producing a quinolonecarboxylic acid derivative represented by

[0009] In this specification, halogen refers to chlorine, bromine, fluorine, and iodine, and alkyl refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, decyl,
Alkyl having 1 to 18 carbon atoms such as dodecyl and octadecyl, and alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, decyloxy, Alkoxy having 1 to 18 carbon atoms such as dodecyloxy and octadecyloxy, and alkenyl include vinyl, allyl, butenyl,
2 or more carbon atoms such as pentenyl, hexenyl, octenyl, etc.
8 alkenyl, haloalkyl is an alkyl having 1 to 8 carbon atoms substituted with at least one halogen, and difluoromethyl, trifluoromethyl, fluoroethyl, trifluoroethyl, etc. are substituted with mono- or dialkyl. Amino is an alkyl group having 1 to 8 carbon atoms.
Amino which may be substituted with two, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, tertiary butylamino, hexylamino, octylamino, dimethylamino, diethylamino,
Dipropylamino, diisopropylamino, dibutylamino, dihexylamino, dioctylamino, etc., cycloalkyl refers to cycloalkyl having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., and acyl refers to formyl. , acetyl, propionyl, butyryl, valeryl, pivaloyl and other acyl having 1 to 5 carbon atoms, alkoxycarbonyl having an alkoxy moiety having 1 to 4 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl,
Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, etc. Aralkyl refers to halogen, alkyl, alkoxy, trifluoromethyl, etc. on the aromatic ring.
It may have 1 to 3 substituents selected from hydroxyl group, nitro, amino, benzyl, 2-, 3- or 4-
Chlorobenzyl, 2-,3- or 4-methylbenzyl, 2-,3- or 4-methoxybenzyl, 2-,3-
or 4-trifluoromethylbenzyl, 2-, 3- or 4-hydroxybenzyl, 2-, 3- or 4-nitrobenzyl, 2-, 3- or 4-aminobenzyl,
Phenylethyl, phenylpropyl, phenylbutyl,
The heterocycle formed by R1 and R2 together with the adjacent nitrogen atom, such as naphthylmethyl, is a 5- to 7-membered heterocycle containing at least one nitrogen atom, including pyrrolidine, piperidine, morpholine, Ester residues that can be hydrolyzed in vivo, such as thiomorpholine, piperazine, and 4-methylpiperazine, are those that can be easily decomposed in vivo to form free carboxylic acids or their salts, and include acetoxymethyl, Alkanoyloxyalkyl esters such as pivaloyloxymethyl, 1-acetoxyethyl, and 1-pivaloyloxyethyl; alkoxycarbonyloxyalkyl esters such as ethoxycarbonyloxymethyl and 1-ethoxycarbonyloxyethyl;
Esters such as phthalidyl and dimethoxyphthalidyl, carbamoyl alkyl esters such as carbamoylmethyl, carbamoylethyl, N-methylcarbamoylmethyl, N,N-dimethylcarbamoylmethyl, N,N-diethylcarbamoylmethyl, alkoxy such as methoxymethyl and methoxyethyl Mention may be made of alkyl esters or 5-methyl-1,3-dioxolen-2-one-4-ylmethyl esters.

The 3-amino-2-benzoyl acrylic acid derivative of general formula (I) can also be obtained as an acid addition salt, a metal salt, etc. As an acid addition salt, it can be obtained by combining it with an inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid. Examples of metal salts include alkali metal salts or alkaline earth metal salts (sodium, potassium, calcium, etc.). salts of copper, zinc, iron, gold, silver, platinum, manganese, etc. as heavy metal salts.

The compound of general formula (I) of the present invention also exists as its corresponding hydrate (monohydrate, hemihydrate, trihydrate, etc.) or other solvates. I can do it.

In the compounds of general formulas (I), (II) and (V), one or two asymmetric carbon atoms exist on the morpholine ring of the 4- or 7-position substituent, so optical isomerism based on this exists. isomers and stereoisomers, and all such isomers and mixtures thereof are included in the present invention.

According to the invention, the 3-amino-2-benzoyl acrylic acid derivative of the general formula (I) is a compound of the general formula (II) or a reactive derivative thereof (acid halides, thiol esters, acid anhydrides, mixed It can be produced by reacting an aminoacrylic acid derivative of general formula (III) with an acid anhydride, ester, acid azide, acid amide, etc.

The reaction is between compound (II) and compound (III)
A method of condensing compound (III) with 0.8 to 3 moles of compound (II), in the absence of a solvent or in the presence of an appropriate solvent, at 30 to 200°C, preferably at 50 to 120°C. C. for 1 to 24 hours. Suitable solvents include toluene, xylene, cyclohexane, dimethylformamide and dimethylsulfoxide. At this time, triethylamine, dimethylaniline, 1,8-diazabicyclo [5.4.0] is used as a deoxidizing agent.
Organic bases such as undec-7-ene or inorganic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate may be used.

Further, according to the present invention, 3- of general formula (I)
The quinolone derivative of general formula (V) can be produced by reacting the amine derivative of general formula (IV) with an amino-2-benzoyl acrylic acid derivative as a synthetic intermediate and then cyclizing it.

The reaction is a method of condensing compound (I) with compound (IV), and this condensation reaction
The reaction is carried out using 1 to 5 times the molar amount of Compound (IV) per mole, without a solvent or in the presence of an appropriate solvent, at 30 to 150°C, preferably 50 to 100°C, for 1 to 6 hours. Suitable solvents include hydrocarbons such as toluene, xylene, cyclohexane, and hexane, alcohols (methanol, ethanol, propanol, butanol, etc.), dimethylformamide, and dimethylsulfoxide.

[0017] In addition, the cyclization reaction is carried out using 1 to 3 times the molar amount of base,
For example, in the presence of potassium carbonate, sodium carbonate, sodium hydride, etc., at 30-150°C, preferably at 30-150°C.
It is carried out at 00°C for 1 to 6 hours. Suitable solvents include alcohol, dioxane, tetrahydrofuran, dimethylformamide and dimethylsulfoxide.

Among the compounds of general formula (I) or (V) obtained by the method of the present invention, compounds in which R3 is alkyl or aralkyl can be deprotected according to the method described in JP-A-2-138278. Among the carboxylic acid compounds of formula (I) or (V), it can be converted to a compound in which R3 is hydrogen. This reaction can be carried out by hydrolysis using an acid or alkali, or by using a catalytic ring element.

Further, in the compound of general formula (I) or (V), R1 is acyl or alkoxycarbonyl (ethoxycarbonyl, tertiary butoxycarbonyl, benzyloxycarbonyl, etc.) and R2 is hydrogen or alkyl, Alternatively, compounds in which R1 is hydrogen and R2 is aralkyl can be similarly deprotected according to a conventional method by hydrolysis or catalytic reduction using an acid or alkali. It can be converted to a compound in which R2 is hydrogen or alkyl.

[0020]

EXAMPLES Next, the present invention will be specifically explained in detail with reference to Examples, but the present invention is not limited to these in any way.

Example 1 (1) 4-(2-acetylaminomethylmorpholino)-
Add 64 ml of thionyl chloride to 32 g of 2,3,5-trifluorobenzoic acid, and after dissolving, add 100 ml of methylene chloride. Stir at room temperature for 2 hours and leave overnight. The formed crystals are collected by filtration to obtain 4-(2-acetylaminomethylmorpholino)-2,3,5-trifluorobenzoic acid chloride hydrochloride. Melting point 151-153℃ (2) 2-dimethylaminoacrylic acid ethyl ester 0
．． 67g of 4-(2-
Add 2.0 g of acetylaminomethylmorpholino)-2,3,5-trifluorobenzoic acid chloride hydrochloride, and
Stir at ~80°C for 4 hours. After washing with water and drying with magnesium sulfate, it is concentrated under reduced pressure to obtain 2-[4-(2-acetylaminomethylmorpholino)-2,3,5-trifluorobenzoyl]-3-dimethylaminoacrylic acid ethyl ester. . NMR (CDCl3, δ (ppm): 1.06 (3H,
t, J=7), 2.01 (3H, s), 2.8 to 4.0
(15H, m), 4.05 (2H, q, J=7), 5.
9 (1H, bs), 7.0-7.25 (1H, m), 7
．． 25 (1H, s)

Example 2 (1) 15 g of 4-(2-ethoxycarbonylaminomethylmorpholino)-2,3,5-trifluorobenzoic acid,
3.6 ml of thionyl chloride, 30 ml of dichloroethane and 3 drops of dimethylformamide are refluxed for 2 hours. The reaction mixture is concentrated under reduced pressure, toluene is added, and concentrated again under reduced pressure to obtain 4-(2-ethoxycarbonylaminomethylmorpholino)-2,3,5-trifluorobenzoic acid chloride. Melting point 78-80℃ (2) 2-dimethylaminoacrylic acid ethyl ester 1
．． 29g, triethylamine 1.1g and toluene 1
4-(2-ethoxycarbonylaminomethylmorpholino)-2,3, obtained in Example 2 (1) to 3 ml of solution.
A solution of 3.8 g of 5-trifluorobenzoic acid chloride and 8 ml of toluene is added, and the mixture is stirred at 70 to 80°C for 4 hours. After washing with water and drying with magnesium sulfate, it was concentrated under reduced pressure to obtain 2-[4-(2-ethoxycarbonylaminomethylmorpholino)-2,3,5-trifluorobenzoyl].
-3-dimethylaminoacrylic acid ethyl ester is obtained. NMR (CDCl3), δ (ppm): 1.06 (3H
, t, J=7), 1.26 (3H, t, J=7), 2.
8-4.0 (15H, m), 4.06 (2H, q, J=
7), 4.14 (2H, q, J=7), 5.0 (1H,
bs), 7.0 to 7.25 (1H, m), 7.26 (1
H,s)

Similarly, the following compounds can be obtained.

Example 3 3-dimethylamino-2-[4-(2-dimethylaminomethylmorpholino)-2,3,5-trifluorobenzoyl]acrylic acid ethyl ester NMR (CDCl3), δ (ppm): 1 .06 (3H
, t, J=7), 2.29 (6H, s), 2.8-4.
0 (15H, m), 4.05 (2H, q, J=7), 7
．． 0-7.25 (1H, m), 7.25 (1H, s)

Example 4 3-dimethylamino-2-[4-(2-formylaminomethylmorpholino)-2,3,5-trifluorobenzoyl]acrylic acid ethyl ester NMR (CDCl3), δ (ppm): 1 .06 (3H
, t, J=7), 2.8 to 4.0 (15H, m), 4.
05 (2H, q, J=7), 7.0-7.25 (1H,
m), 7.25 (1H, s)

Example 5 2-[4-[2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholino]-2,3,5-trifluorobenzoyl]-3-dimethylaminoacrylic acid ethyl ester NMR ( CDCl3), δ (ppm): 1.06 (3H
, t, J=7), 1.27 (3H, t, J=7), 3.
00 (3H, s), 2.8-4.0 (15H, m), 4
．． 05 (2H, q, J = 7), 7.0-7.25 (1H
, m), 7.25 (1H, s)

Example 6 2-[4-(2-acetylaminomethylmorpholino)-
1.2 cyclopropylamine was added to a solution of 8.68 g of 2,3,5-trifluorobenzoyl]-3-dimethylaminoacrylic acid ethyl ester and 40 ml of ethanol.
Add a solution of g and 8 ml of ethanol under ice-cooling. After stirring at room temperature for 2 hours and concentrating under reduced pressure, 33 ml of dimethylformamide and then 2.3 g of potassium carbonate powder were added, and the mixture was stirred at 60°C for 3 hours. 7-(2-acetylaminomethylmorpholino)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo was obtained by adding water to the reaction solution, collecting the formed crystals by filtration, and drying them. 3-quinolinecarboxylic acid ethyl ester is obtained. Melting point 216-218℃

Example 7 2-[4-[2-ethoxycarbonylaminomethylmorpholino]-2,3,5-trifluorobenzoyl]-3
-Dimethylaminoacrylic acid ethyl ester 8.68g
A solution of 1.2 g of cyclopropylamine and 8 ml of ethanol is added to a solution of 40 ml of ethanol under ice cooling. After stirring at room temperature for 2 hours and concentrating under reduced pressure, 33 ml of dimethylformamide and then 2 ml of potassium carbonate powder were added.
．． Add 3g and stir at 60°C for 3 hours. By adding water to the reaction solution, filtering and drying the generated crystals, 1.
-cyclopropyl-7-(2-ethoxycarbonylaminomethylmorpholino)-6,8-difluoro-1,4-
Dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester is obtained. Melting point 149-151℃

Example 8 2-dimethylaminoacrylic acid ethyl ester 1.29
g, triethylamine 2.13g and toluene 20m
3.87 g of 4-(2-acetaminomethylmorpholino)-2,3,5-trifluorobenzoic acid chloride hydrochloride obtained in Example 1 (1) was added to the solution of 70 to 80°C.
Stir for 4 hours. After washing with water and drying with magnesium sulfate, add 0.57 g of cyclopropylamine and
．． Stir for 5 hours. After washing with water, concentrate under reduced pressure, add 15 ml of dimethylformamide, and then add 1.38 ml of potassium carbonate.
g and stirred at 50-60°C for 1.5 hours. . By adding water to the reaction solution, filtering and drying the generated crystals, 7-(2-acetylaminomethylmorpholino)
-1-cyclopropyl-6,8-difluoro-1,4-
Dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester is obtained. The melting point was consistent with that obtained in Example 6.

Example 9 In a solution of 10 g of the 4-(2-ethoxycarbonylaminomethylmorpholino)-2,3,5-trifluorobenzoic acid chloride obtained in Example 2 (1) and 50 ml of toluene, 2-dimethylamino Acrylic acid ethyl ester 3.
38g, triethylamine 2.92g and toluene 2
Add 0 ml of solution and stir at 70-80°C for 4 hours. After washing with water and drying with magnesium sulfate, 1.5 g of cyclopropylamine was added, and the mixture was stirred at room temperature for 1.5 hours. After washing with water, concentrate under reduced pressure and add 34 ml of dimethylformamide.
Next, 3.63 g of potassium carbonate is added, and the mixture is stirred at 50 to 60°C for 1.5 hours. 1-Cyclopropyl-
7-(2-Ethoxycarbonylaminomethylmorpholino)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester is obtained. The melting point was consistent with that obtained in Example 1.

Similarly, the following compounds of Examples 10, 11 and 12 can be obtained from the compounds of Examples 3, 4 and 5.

Example 10 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2-dimethylaminomethylmorpholino)
-4-oxo-3-quinolinecarboxylic acid ethyl ester, melting point 168-169°C

Example 11 1-Cyclopropyl-6,8-difluoro-7-(2-
formylaminomethylmorpholino)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester

Example 12 1-cyclopropyl-7-[2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholino]-6,8
-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, melting point 122-124
℃

[0035]

Effect of the invention: 3-amino-2 of general formula (I) of the present invention
- The novel method for producing quinolone carboxylic acid derivatives via benzoyl acrylic acid derivatives can safely produce the desired product in high yield and in a short reaction time under mild conditions. Therefore, it is industrially more useful than conventional methods.

Claims (4)

[Claims] Claim 1: General formula [Formula 1] [In the formula, R1 and R2 are the same or different and represent hydrogen, alkyl, cycloalkyl, aralkyl, acyl or alkoxycarbonyl, or R1 and R2 are bonded to each other and are adjacent R3 represents hydrogen, alkyl, aralkyl or an ester residue that can be hydrolyzed in vivo, R4 and R5 represent alkyl, R6 represents hydrogen or alkyl, X
represents hydrogen, halogen or alkyl, and n represents an integer of 1 to 3. ] A 3-amino-2-benzoyl acrylic acid derivative represented by: Claim 2: General formula [Formula 2] [In the formula, each symbol has the same meaning as defined in Claim 1. ] or a reactive derivative thereof, the compound represented by the general formula [Image Omitted] [wherein each symbol has the same meaning as defined in claim 1]. [In the formula, each symbol has the same meaning as defined in claim 1]. ] A method for producing a 3-amino-2-benzoyl acrylic acid derivative. Claim 3: General formula [Image Omitted] [In the formula, each symbol has the same meaning as defined in Claim 1. [In the formula, R7 is alkyl, cycloalkyl, haloalkyl, alkenyl, mono- or dialkylamino, phenyl, or a substituent of halogen, alkyl, alkoxy, hydroxyl, nitro, or amino]. Indicates a phenyl group having 1 to 3 atoms. [In the formula, each symbol is defined in claim 1] [In the formula, each symbol is as defined in claim 1] is synonymous with ] A method for producing a quinolone carboxylic acid derivative represented by Claim 4: General formula [Image Omitted] [In the formula, each symbol has the same meaning as defined in claim 1. ] or a reactive derivative thereof, the compound represented by the general formula [Image Omitted] [wherein each symbol has the same meaning as defined in claim 1]. ] An aminoacrylic acid derivative represented by the general formula [Image Omitted] is reacted, and each symbol has the same meaning as defined in claim 1. ] A 3-amino-2-benzoyl acrylic acid derivative represented by the general formula [Image Omitted] is obtained, and R7 has the same meaning as defined in claim 3. [In the formula, each symbol is defined in claim 1] [In the formula, each symbol is as defined in claim 1] is synonymous with ] A method for producing a quinolone carboxylic acid derivative represented by