JP2990903B2 - Method for producing 4-oxoquinoline-3-carboxylic acids - Google Patents

Abstract

PURPOSE:To obtain the subject compounds useful as a quinolinecarboxylic acid-based germicide in high purity and yield by reacting a 3-alkylamino-2- benzoyl-acrylic acid ester with a titanium compound. CONSTITUTION:A compound expressed by formula I (R<1> is 1-5C alkyl or 2-5C alkenyl; R<2> is H, F, amino, nitro, etc.; Y is N or C-R<3>; R<3> is H, halogen, methoxy which can be expressed by F, lower alkyl or benzyloxy; R<4> is lower alkyl which can be substituted by F, cyclopropyl, etc.; X and Z are F or Cl) is reacted with a compound expressed by the formula Ti(OR)4 (R is lower alkyl or alkenyl) in a solvent (e.g. toluene) at ambient temperature to 200 deg.C to afford the objective compounds expressed by formula II. The titanium compound is used in a molar amount of 1-1.5 times based on the compound expressed by formula I. Since cyclizing reaction can be carried out under neutral conditions, side reaction hardly occurs without forming by-products.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 4-oxoquinoline-3-carboxylic acids represented by the formula (II) described below are useful as quinoline carboxylic acid fungicides, and the present invention relates to 4-oxoquinoline-3-carboxylic acids ( II) in a high yield and high purity.

[0002]

2. Description of the Related Art Conventionally, 4-oxoquinoline-3-carboxylic acids (II) have been converted to 3-alkylamino-2-benzoyl-acrylates represented by the following formula (I):
(A) Alkali metal carbonate (JP-A-62-252772)
JP-A-63-198664, JP-A-60-728
No. 85, JP-A-61-1682, JP-A-64-404
No. 60 and JP-A-61-44866).
(B) Strong organic bases such as diazabicycloundecene (DBU) (JP-A-54-132582 and JP-A-1
JP-A-246265), (c) sodium hydride (see JP-A-61-44866), or (d) potassium hydroxide (see JP-A-54-132582).
Is known.

However, in these methods, the ester group is hydrolyzed during the reaction, resulting in a large amount of free 4-oxoquinoline-3-carboxylic acid as a by-product, an expensive reagent, dimethylformamide, dimethylformamide, and the like. A reaction solvent such as sulfoxide, which is difficult to recover, must be used, or a by-product has been produced which has reacted with fluorine substituted on the nucleus. These causes are all caused by the reaction being strongly basic.

[0004]

SUMMARY OF THE INVENTION In view of the above-mentioned problems of the conventional methods, the present invention has been studied on a cyclization reaction under substantially neutral conditions, and has been carried out to obtain the desired 4-oxoquinoline-
A method for producing 3-carboxylic acids (II) in high yield and high purity has been found.

[0005]

SUMMARY OF THE INVENTION The method of the present invention comprises a compound of the formula (I)

[0006]

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(Wherein R ¹ represents an alkyl group or alkenyl group having 1 to 5 carbon atoms, R ² represents a hydrogen atom, a fluorine atom, an amino group, a nitro group or a benzylamino group;
Y represents a nitrogen atom or a C—R ³ group, R ³ represents a hydrogen atom,
A halogen atom or a fluorine atom represents a methoxy group, a lower alkyl group or a benzyloxy group which may be substituted by 1 to 3 atoms, and R ⁴ represents a lower alkyl group, a cyclopropyl group or a fluorine atom which may be substituted by a fluorine atom. An atom-substituted phenyl group, N-formyl-N-methylamino group or N
-Acetyl-N-methylamino group, and X and Z each represent a fluorine atom or a chlorine atom).
An alkylamino-2-benzoyl-acrylate is represented by the formula Ti (OR) ₄ (III), wherein R represents a lower alkyl group or an alkenyl group.
(II) characterized by reacting with a titanium compound represented by the formula:

[0008]

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Wherein R ¹ , R ² , R ⁴ , Y and X have the same meanings as described above.
This is a method for producing carboxylic acids.

In the above formula, examples of the alkyl group of R ¹ and R ³ include methyl, ethyl, propyl and butyl, and examples of the alkenyl group of R ¹ include allyl and methallyl. Examples of the halogen atom for R ³ include fluorine, chlorine and bromine, and examples of the methoxy group optionally substituted by a fluorine atom include methoxy, fluoromethoxy, difluoromethoxy and trifluoromethoxy. Examples of the lower alkyl group which may be substituted by a fluorine atom of R ⁴ include ethyl and 2-fluoroethyl. Examples of the phenyl group substituted by a fluorine atom include:
4-fluorophenyl, 2,4-difluorophenyl and the like can be mentioned.

Examples of the tetraalkoxytitanium used in the present invention include tetramethoxytitanium, tetraethoxytitanium, tetrapropoxytitanium, tetraisopropoxytitanium, tetrabutoxytitanium, tetraisobutoxytitanium and the like. Are tetraallyloxytitanium, tetramethallyloxytitanium and the like.

The amount of the titanium compound (III) used is 3
0.01 to 1.5 times mol of the alkylamino-2-benzoyl-acrylates (I) is preferred. If the amount used is larger than this, the reaction proceeds rapidly, but economy and post-treatment become difficult.

The reaction is carried out in a solvent and the titanium compound (II
Any solvent can be used as long as it dissolves I) and 3-alkylamino-2-benzoyl-acrylates (I).
For example, aromatic hydrocarbons such as benzene, toluene, and xylene; dichloromethane, chloroform, dichloroethane,
Chlorinated hydrocarbons such as chlorobenzene; ethers such as tetrahydrofuran and dioxane; acetonitrile;
An aprotic polar solvent such as dimethylformamide and dimethylsulfoxide can be used. When alcohols are used as the solvent, transesterification occurs. By utilizing this, a cyclization reaction and a transesterification reaction can be carried out simultaneously to obtain a desired ester, and the present invention includes a method for producing such a transesterified compound of the formula (II). is there. The amount of the solvent used is preferably in the range of 1 to 60% by weight / volume.

The reaction is carried out at a temperature in the range of room temperature to 200 ° C., but the reactivity varies depending on the type of the substituent of the 3-alkylamino-2-benzoyl-acrylates. Is carried out by raising the reaction temperature. The reaction time is greatly affected by the reaction temperature and the substituents of the 3-alkylamino-2-benzoyl-acrylates, but is usually completed in 0.5 to 36 hours.

From the reaction solution, the desired product having a sufficiently high purity can be obtained by a usual operation. However, depending on the desired compound, it is recommended that the solvent is concentrated, washed with a dilute acid to remove the titanium compound, and then recrystallized. You. Equation (II) obtained in this way
Examples of the 4-oxoquinoline-3-carboxylic acid ester include methyl, ethyl, propyl, butyl, allyl and methallyl esters of the acids shown in Table 1.

[0016]

[Table 1]

[0017]

According to the method of the present invention, the cyclization reaction can be carried out under substantially neutral conditions, so that various side reactions under basic conditions as in the prior art hardly occur,
Even if the quinolone ring has a substituent which reacts with an alkali, it can be reacted without producing a by-product, so that 4-oxoquinoline-3-carboxylic acid ester (II) having high yield and high purity can be obtained. can get.

[0018]

Next, the present invention will be described more specifically with reference to examples and reference examples. Example 1 Allyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate

3-cyclopropylamino-2- (2,
4,5-trifluoro-3-methoxybenzoyl) allyl acrylate ester 0.36g was dissolved in toluene _{20ml, Ti (OCH 2 CH =} CH 2) 4 0.08g was added, followed by stirring under reflux heating. After cooling, toluene was removed under reduced pressure and the mixture was concentrated. The residue was diluted with 2 ml of dichloromethane and 1 ml of hexane.
Recrystallization from 0 ml gave 0.29 g of the title compound. Yield 87%. Colorless needle crystals. 146-147 ° C

Incidentally, 12% of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid was by-produced. Melting point 18
4-185 ° C.

Example 2 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester

3-cyclopropylamino-2- (2,
Use of 4,5-trifluoro-3-methoxybenzoyl) acrylic acid ethyl _{ester, Ti (OC 2 H 5)} 4
The reaction was carried out in the same manner as in Example 1 except that 0.06 g was used to produce the title compound. Yield 65%. Colorless needle crystals. 180-182 ° C.

Incidentally, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid was by-produced by 12%.

Example 3 1-Cyclopropyl-6,7,8-trifluoro-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid allyl ester

3-cyclopropylamino-2- (2,
The title compound was produced from allyl 3,4,5-tetrafluorobenzoyl) acrylate by reacting in the same manner as in Example 1. Yield 65%. Colorless needle crystals. Melting point 1
45-146 ° C.

Example 4 Allyl 5-amino-1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate

0.57 g of ethyl 3-cyclopropylamino-2- (6-amino-3-difluoromethoxy-2,4,5-trifluorobenzoyl) acrylate
Ti and a mixture of allyl alcohol 1ml and toluene _{20ml (O-iC 3 H 7} ) 4 0.03g was added, under reflux for two
Stirred for hours. The produced ethanol was distilled off together with toluene, 10 ml of allyl alcohol was added, and stirring was continued under reflux for 2 hours. The same work-up as in Example 1 was performed to obtain the title compound in a yield of 51.6%. Yellow needle-like crystals. 249-250 ° C.

Incidentally, 5-amino-1-cyclopropyl-
6,7-difluoro-8-difluoromethoxy-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid is 3
6.9% (HPLC area%) was by-produced.

Example 5 Allyl 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-5-nitro-1,4-dihydro-4-oxoquinoline-3-carboxylate

The allyl ester of 3-cyclopropylamino-2- (3-difluoromethoxy-6-nitro-2,4,5-trifluorobenzoyl) acrylate was reacted in the same manner as in Example 4 to give the title compound. Yield 44.9%
I got it. Pale yellow needle-like crystals. 234-235 ° C.

Incidentally, 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-
5-Nitro-4-oxoquinoline-3-carboxylic acid ethyl ester was by-produced at 14.8%.

Example 6 7-Chloro-1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid allyl ester

3-cyclopropylamino-2- (2,4
-Dichloro-5-fluorobenzoyl) acrylic acid was reacted in the same manner as in Example 1 to obtain the title compound in a yield of 68.4%. Colorless scaly crystals. Melting point 1
87-188 ° C.

It should be noted that 7-chloro-1-cyclopropyl-
6-Fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was by-produced at 28.7%.

Example 7 1-Cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid allyl ester

3-cyclopropylamino-2- (2,
The reaction was carried out in the same manner as in Example 1 from allyl 3,4,5,6-pentafluorobenzoyl) acrylate to obtain the title compound in a yield of 76.2%. Colorless scaly crystals. 125-126 ° C.

Incidentally, 1-cyclopropyl-5,6,7,
8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was produced as a by-product of 14.2%.

Example 8 Allyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-difluoromethoxy-4-oxoquinoline-3-carboxylate

3-cyclopropylamino-2- (2,
The reaction was carried out in the same manner as in Example 1 using 4,5-trifluoro-3-difluoromethoxybenzoyl) acrylic acid allyl ester to obtain the title compound in a yield of 85%. Colorless needle crystals. 202-203 ° C.

Incidentally, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (melting point: 202-207 ° C.) was by-produced by 14%.

Reference Example 1 Allyl 3-cyclopropylamino-2- (2,4,5-trifluoro-3-methoxybenzoyl) acrylate

It was produced as follows according to the method described in JP-A-63-316575. 5 g of 3-dimethylaminoacrylic acid allyl ester was dissolved in 11 ml of anhydrous tetrahydrofuran, and 3.4 g of triethylamine was added.
The mixture was heated and stirred under reflux. To this solution was added 3-methoxy-2,
A solution obtained by dissolving 11.3 g of 4,5-trifluorobenzoic acid chloride in 2 ml of anhydrous tetrahydrofuran was added dropwise.
The mixture was stirred under reflux for 2 hours. After cooling, the triethylamine hydrochloride formed is removed by filtration, the filtrate is washed with 5 ml of water,
The tetrahydrofuran was removed under reduced pressure and concentrated. Purification by silica gel column chromatography gave 3-dimethylamino-2- (2,4,5-trifluoro-3-
7. methoxy-benzoyl) acrylic acid allyl ester
8 g were obtained as a colorless oil. 3.43 g of this acrylic acid derivative was dissolved in 4 ml of anhydrous tetrahydrofuran, 0.62 g of cyclopropylamine was added, and the mixture was heated to 50 ° C. and stirred for 2 hours. After cooling, tetrahydrofuran was removed under reduced pressure and the mixture was concentrated to obtain 3.5 g of the title compound as a colorless oil.

Example 9 8-benzyloxy-6,7-difluoro-1- (N-
(Acetyl-N-methylamino) -1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid ethyl ester

180 mg of ethyl 3- (2-acetyl-2-methylhydrazino) -2- (2,4,5-trifluoro-3-benzyloxybenzoyl) acrylate
Is dissolved in 5 ml of toluene, and 30 mg of Ti (OC ₂ H ₅ ) ₄ is dissolved.
Was added and the mixture was heated and stirred under reflux for 3 hours. After cooling, toluene was removed under reduced pressure, and the mixture was concentrated. The residue was purified by silica gel chromatography (eluent: ethyl acetate) to obtain 115 mg of the title compound. Melting point 166-168 [deg.] C.

¹ H NMR (200 MHz, CDCl ₃ ) 1.30 to 1.4
_{5 (m, 3H, CH 2} C H 3), 1.65,1.93 (2 pieces of s, 3H, COCH ₃₎
, 3.28,3.31 (two _{s, 3H, N-CH 3} ), 4.30~4.46
_{(M, 2H, C H 2} CH 3), 5.00~5.43 (m, 2H, OC H 2 Ph), 7.37
7.57.53 (m, 5H, Ph), 8.00 to 8.15 (m, 1H, aromatic proton), 8.15, 8.27 (two s, 1H, N-CH =), MS (CI): 43
1 (M + 1), 360, 270, 91, 74

Reference Example 2 3-benzyloxy-2,4,5-trifluorobenzoic acid

3-Hydroxy-2,4,5-trifluorobenzoic acid (0.2 mol), 200 ml of methanol and 2
A mixture of a methanol solution (0.4 mol) of 8% sodium methoxide was stirred to obtain a homogeneous solution. To this was added benzyl chloride (0.4 mol), and the mixture was stirred under reflux for 5 hours. After cooling, methanol was removed under reduced pressure, and 5%
A NaOH solution (0.5 mol) was added, and the mixture was heated and stirred at 60 ° C. for 2 hours. The mixture was extracted twice with 100 ml of toluene, and concentrated hydrochloric acid was added to the remaining water tank until the pH became 4 or less. After cooling, the precipitated solid was filtered off, dried and recrystallized from hot toluene to give the title compound. Yield 33 g. 135-136
° C.

¹ H NMR (400 MHz, CDCl ₃ ) 5.23 (s,
_{2H, CH 2), 7.31~7.44 (} m, 5H, Ph), 7.53 (m, 1H, Ar-
H), 10.5 (br, 1H , CO 2 H), MS (CI): 283 (M + 1), 91

Reference Example 3 3-benzyloxy-2,4,5-trifluorobenzoic acid chloride

6.5 g of 3-benzyloxy-2,4,5-trifluorobenzoic acid, 0.1 of dimethylformamide
To a mixture of 50 ml of toluene and 50 ml of toluene, 3.6 g of thionyl chloride was added dropwise under heating (80 ° C.), and the mixture was stirred at the same temperature for 3 hours. The solution was concentrated under reduced pressure, and the residue was
It dissolved in ml and filtered the insoluble matter. The filtrate was concentrated to obtain 6.0 g of the title compound as pale yellow crystals. Melting point 46
４７47.5 ° C. Recrystallization from n-hexane gave 5.7 g of the target compound as colorless crystals.

Reference Example 4 3- (2-acetyl-2-methylhydrazino) -2-
(2,4,5-trifluoro-3-benzyloxybenzoyl) acrylic acid ethyl ester

1.43 g of 3-dimethylaminoallylic acid ethyl ester, 1.06 g of triethylamine and THF
A 5 ml mixture was heated to 60 DEG C. and a solution of 3.0 g of 3-benzyloxy-2,4,5-trifluorobenzoic acid chloride in 5 ml of THF was added dropwise. Heating and stirring were continued under reflux for 2 hours. After cooling, the precipitate formed was filtered off and the solid was washed with 5 ml of THF. Combine the filtrate and washings,
To 1-acetyl-1-methylhydrazine (J.O.
rg. Chem. 41 2733 synthesized by the method of 1976)
0.90 g was added, and the mixture was stirred at the same temperature for 2 hours. After cooling, the solvent was removed under reduced pressure, and the residue was subjected to silica gel chromatography (eluent: n-hexane: ethyl acetate = 1: 1) to obtain 2.0 g of the title compound. Light yellow viscous syrup.

[0053] _{^{1 HNMR (200MHz, CDCl 3)}} 0.96,
1.10 (two sets of _{t, 3H, CH 2 C H} 3), 2.14,2.19 (2 pieces of s,
3H, COCH ₃ ), 3.28, 3.32 (two s, 3H, N-CH ₃ ), 3.
99 to 4.20 (two sets of _{q, 2H, C H 2 CH} 3), 5.19 (s, 2H, CH 2
Ph), 6.90-7.15 (m, 1H, aromatic proton), 7.31-7.
_{50 (m, 5H, C 6} H 5), 7.90,8.07 (2 pieces of d, 1H, N-CH
=, Change to 2 s by adding D ₂ O), 10.30, 11.75 (2
D, 1H, NH, disappeared upon addition of D ₂ O), MS (CI): 451 (M + 1),
450, 431, 380, 360, 310, 220, 187, 91, 74

Continuation of the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C07D 215/56 C07D 471/04 CA (STN)

Claims (1)

(57) [Claims] 1. A compound of the formula (I) (Wherein, R ¹ represents an alkyl group or alkenyl group having 1 to 5 carbon atoms, and R ² represents a hydrogen atom, a fluorine atom, an amino group,
Represents a nitro group or a benzylamino group, Y represents a nitrogen atom or a C—R ³ group, and R ³ represents a methoxy group or a lower alkyl group which may be substituted with 1 to 3 hydrogen atoms, halogen atoms or fluorine atoms. or a benzyl group, R ⁴
Is a lower alkyl group optionally substituted with a fluorine atom, a cyclopropyl group or a phenyl group substituted with a fluorine atom,
N-formyl-N-methylamino group or N-acetyl-
A 3-alkylamino-2-benzoyl-acrylate represented by the formula: Ti (OR) ₄ (III) (wherein X and Z each represent a fluorine atom or a chlorine atom). , R represents a lower alkyl group or an alkenyl group)
Formula (II) characterized by reacting with a titanium compound represented by the following formula: (Wherein R ¹ , R ² , R ⁴ , Y and X have the same meanings as described above), and a process for producing 4-oxoquinoline-3-carboxylic acids represented by the formula: