JP2952706B2 - Method for producing 4-quinolone derivative - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a new method for producing a 4-quinolone derivative.

2. Description of the Related Art A 4-quinolone derivative represented by the following general formula (III) is a useful compound conventionally known as an important intermediate for synthesizing various antibacterial agents.

[Wherein, R ¹ and R ² are the same or different and are each a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cycloalkyl group,
Hydroxyl group, protected hydroxyl group, nitro group, halogen atom,
A cyano group, an amino group, an ester group, a lower alkyl group substituted with an ester group, a lower alkylamino group substituted with one or two linear or branched alkyl groups having 1 to 4 carbon atoms, a lower alkoxy group or 5 which may have a substituent
A 6-membered or 6-membered nitrogen-containing multiple ring group, and each R ¹ may be different from each other. As a method for producing a 4-quinolone derivative, the following method is conventionally known.

(1) A method in which 3-arylaminomethylidenemalonates are thermally closed at high temperatures [for example, J. Heterocy]
clic Chem., 21, 1857 (1984)].

(2) A method of forming a ring using an intramolecular substitution reaction of 3- (2-haloaryl) -3-keto-2-aminomethylidenepropionates, for example, J. Med. Chem., 28, 1558.
(1985)].

However, in the above method (1), generally, 200 ° C.
The above-mentioned high temperature is required and it is not applied to a compound having a thermally unstable functional group. Other methods require stoichiometric use of effective reagents, which is problematic for industrial practice.

Problems to be Solved by the Invention It is an object of the present invention to provide a method which is free from the drawbacks of the above-mentioned conventional method, is safe and simple in operation, is industrially advantageous, and has a high yield and a high purity by the general formula ( Another object of the present invention is to provide a method capable of producing the quinolone carboxylic acid derivative represented by III).

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the problems of the above-mentioned conventional methods. As a result, the carbonylation method using a palladium catalyst is an excellent production method suitable for the purpose of the present invention. I found that it could be a law.

That is, according to the present invention, 4 represented by the general formula (III)
-The quinolone derivative can be obtained by a simple operation by carbonylating the aniline derivative represented by the general formula (I),
Moreover, it can be produced with high yield and high purity.

In the present specification, as the lower alkyl group, a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group,
Examples thereof include a tertiary-butyl group, a pentyl group, and a neobentyl group. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Hydroxyl-protecting groups include: Protective Groups in Organic Synthesis, Thedora
Chapter 2 (10-72) of W. Greene
Page)). Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the lower alkylamino group in which one or two linear or branched alkyl groups having 1 to 4 carbon atoms are substituted include a methylamino group, an ethylamino group, a diethylamino group, a propylamino group, a dipropylamino group, Examples thereof include a tertiary-butylamino group, a di-tertiary-butylamino group, and a tertiary-butylethylamino group. As the 5- or 6-membered nitrogen-containing heterocyclic group, And the like, and a group bonded on a ring nitrogen atom or a carbon atom. As the substituent in the nitrogen-containing heterocyclic group, a halogen atom, a hydroxyl group, a lower alkoxy group, (for example, a methoxy group ethoxy group, a propoxy group,
Isopropoxy group, butoxy group, isobutoxy group, tertiary-butoxy group, etc.), nitro group, cyano group, amino group, and linear or branched alkyl group having 1 to 4 carbon atoms.
Two substituted lower alkylamino groups (specifically, methylamino, ethylamino, diethylamino, propylamino, dipropylamino, tertiary-butylamino, di-tertiary-butylamino, tertiary-butylethylamino, etc. ), Wherein the linear or branched alkyl group having 1 to 4 carbon atoms is 1 to
Three substituted lower alkylammonium salts (specifically, trimethylammonium, triethylammonium, methyldiethylammonium, triisobutylammonium, tri-tert-butylammonium, etc.), an acyl group (specifically, formyl, acetyl, Propionyl, butyryl, isobutyryl, pivaloyl, benzoyl, para-methylbenzoyl, para-methoxybenzoyl, para-chlorobenzoyl, para-nitrobenzoyl group, etc.) acyloxy group (specifically, formyloxy,
Acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy, benzoyloxy, para-methylbenzoyloxy, para-methoxybenzoyloxy, para-chlorobenzoyloxy, para-nitrobenzoyloxy and the like. These substituents may have 1 to 5 substituents on the heterocyclic ring.

In the present invention, the aniline derivative represented by the general formula (I) is carbonylated using a palladium catalyst and carbon monoxide in the presence of the acetylene derivative represented by the general formula (II).

The palladium catalyst used in the present invention is not particularly limited, and may be divalent or zero-valent, and may be used alone or in the form of a complex. These palladium catalysts
It may be in the form of a salt or used in combination with a suitable ligand. Examples of the salt include chlorinated products, brominated products, iodides, acetates, sulfates, perchlorates, acetylacetone salts and phosphine complexes thereof. Examples of the zero-valent complex include tetrakistriphenylphosphine palladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium chloroform, tris (dibenzylideneacetone) dipalladium chloroform, and tris ( Examples thereof include tribenzylideneacetylacetone) dipalladium and tris (tribenzylideneacetylaceton) dipalladium chloroform. In the present invention, the amount of the palladium catalyst is not particularly limited, and is appropriately used within a range of 0.001 to 50 mol%, but is preferably used within a range of 0.1 to 10 mol%. Examples of the ligand used together with the divalent complex and the zero-valent complex include ordinary triphenyl phosphine, tri (o-tolyl) phosphine, tri (p-tolyl) phosphine, tri (p-methoxyphenyl) phosphine and the like. Coordination ligand,
1,2-bis-diphenylphosphinoethane, 1,3-bis-
Phosphines such as bidentate ligands such as diphenylphosphinopropane, 1,4-bis-diphenylphosphinobutan, and diphenylphosphinoferrocene; trimethylphosphite, triethylphosphite, triisopropylphosphite, triphenylphosphite, and the like Can be exemplified. The amount of the ligand may be an amount that stabilizes the catalyst, and is usually used in an amount of 1 to 10 equivalents to the catalyst. The catalyst may be a supported one, and 5% -palladium / carbon, 10% -palladium / carbon, etc., which are well known as hydrogenation catalysts, may be used. The reaction proceeds quickly when a base is present. Examples of the base include organic bases such as ethylamine, diethylamine, triethylamine, and pyridine; inorganic salts such as potassium carbonate and sodium carbonate; and acetates such as potassium acetate and sodium acetate. The amount of such a base may be used in the range of 1 to 5 equivalents as long as the acid generated in the system is neutralized. The solvent is not always necessary, but it is better to use an appropriate amount from the viewpoint of stirring efficiency. The amount of the solvent to be used is not particularly limited, and is appropriately determined under reaction conditions and the like. As the solvent, those capable of dissolving the raw material enamine derivative are preferable. Specific examples of such a solvent include tetrahydrofuran, dimethylformamide, acetonitrile, dimethylsulfoxide, benzene, toluene, and the like, and the reaction, which may be a mixed solvent thereof, is performed under a carbon monoxide atmosphere. Is 1-20
0 kg / cm ² , particularly preferably 1 to 70 kg / cm ²
It is carried out in cm ^2.

The concentration of the reaction sample in the solvent is not particularly limited, but a higher concentration is preferable from the viewpoint of reaction efficiency. The reaction temperature is usually in the range of 0 to 200 ° C, and preferably in the range of 50 to 150 ° C. The reaction time is appropriately selected according to the reaction raw material concentration, carbon monoxide pressure, catalyst concentration and other reaction conditions.

Effect of the Invention According to the present invention, 4-
A quinolone derivative can be produced in high purity and high yield without performing a special purification operation.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited to the following Examples as long as the gist is not exceeded.

Example 1 Compound (Ia) (213 mg, 0.97 mmol), Compound (II
a) A solution of (0.2 ml, 1.82 mmol) and dichlorobistriphenylphosphine palladium (36, 2 mg, 0.05 mmol) in diethylamine (3 ml) is reacted at 120 ° C. for 6 hours under carbon monoxide pressure (20 kg / cm ² ). After concentration, methylene chloride is added and washed with water. The organic layer is dried (sodium sulfate), concentrated and purified by column chromatography to obtain compound (IIIa) (193 mg, 90%).

^{IR (KBr); 3460,1636,1599,1584,1549,1506cm -1 1} H-NMR ( methanol _{-d 4) δppm; 6.58 (s} , 1H) 7.40-7.82 (m, 8H) 8.29 (d, J = 7.90 Hz, 1 H) ¹³ C-NMR; 108.48, 119.71, 125.40 125.75, 125.97.128.55 (2C), 130.29 (2C), 131.93, 133.70, 135.46, 141.95, 153.57, 180.64 The results obtained in the same manner as described above were obtained. It is shown in Table 1 below.
The respective spectrum data are shown together.

^{IR (KBr); 3426,1632,1599,1580,1543,1504cm -1 -1} H-NMR (DMSO-d 6) δppm; 3.84 (s, 3H) 6.31 (br, 1H) 7.08-7.18 (m, 2H ) 7.32 (ddd, J = 1.02, 6.93, 8.03 Hz, 1H) 7.64 (ddd, J = 1.43, 6.93, 8.33 Hz, 1H) 7.68-7.83 (m, 3H) 8.09 (dd, J = 1.43, 8.03 Hz, 1H) 11.69 (br, 1H) 13 C-NMR (DMSO-d 6); 55.49,106.61,114.51 (2C), 118.81,123.24,124.79,1
24.90,126.31,129.01 (2C), 131.78,140.65,149.84,16
1.18,177.02 ^{IR (KBr); 3444,1719,1638,1599,1578,1549,1512cm -1 -1} H-NMR (DMSO-d 6) δppm; 1.34 (t, J = 7.08Hz, 3H) 4.35 (q, J = 7.08Hz, 2H) 6.40 (d, J = 1.46Hz, 1H) 7.35 (ddd, J = 1.17,6.85,8.03Hz, 1H) 7.68 (ddd, J = 1.32,6.85,8.01Hz, 1H) 7.78 (brd, J = 8.01Hz, 1H) 7.96-8.14 ( m, 5H) 11.86 (br, 1H) 13 C-NMR (DMSOP-d 6); 14.29,61.25,108.13,118.94,123,62,124.88,125.08,1
28.01 (2C), 129.73 (2C), 131.49,132.16,138.53,140.
65,148.88,165.31,177.11 ^{IR (KBr); 3464,1636,1601,1557,1510cm -1 1} H-NMR (DMSO-d 6) δppm; 6.12 (s, 2H) 6.32 (s, 1H) 7.09 (d, J = 8.05Hz, 1H 7.27−7.42 (m, 3H) 7.62 (ddd, J = 1.35,6.87,8.30Hz, 1H) 7.75 (d, J = 1.30Hz, 1H) 8.07 (dd, J = 1.35,8.05Hz, 1H) ¹³ C _{-NMR (DMSO-d 6);} 101.84,106.68,107.63,108.71,119.11,121,88,123.2
2,124.66,124.78,128.29,131.69,140.86,147.92,149.1
6,149.97,176.69 ^{IR (KBr); 3432,1642,1599,1547,1502cm -1 1} H-NMR ( methanol _{-d 4) δppm; 0.88 (t} , J = 6.32Hz, 3H) 1.25-1.41 (m, 6H) 1.65-1.75 (M, 2H) 2.68 (t, J = 7.69Hz, 2H) 6.22 (s, 1H) 7.36 (ddd, J = 1.39, 6.79, 8.18Hz, 1H) 7.60 (brd, J = 8.39Hz, 1H) 7.71 ( ddd, J = 1.60,6.79,8.39Hz, 1H) 8.32 (dd, J = 1.60,8.18Hz, 1H) 13 C-NMR ( methanol -d _4); 12.48,21.68,28.02,28.25,30.74,33.10,106.92 , 117.1
8,123.14,123.58,123.79,131.47,139.70,155.22,178.71 IR ^{(neat); 3380,1638,1603,1557,1514cm -1 1 H-NMR} ( methanol _{-d 4) δppm; 1.51-1.83 (m} , 6H) 3.49-3.96 (m, 2H) 4.52-4.76 (m, 3H) 6.36 (s, 1H) 7.30-7.38 (m, 1H) 7.59-7.64 (m, 2H) 8.21 (d, J = 8.24Hz, 1H) 13 C-NMR ( methanol -d _4); 18.33,24.42, 29.39,61.48,64.58,98.17,105.96,117.4
2,123.16,123.90,124.02,131.55,139.48,150.46,178.65 ^{IR (KBr); 3472,1630,1597,1562,1512cm -1 1} H-NMR (CDCl 3) δppm; 1.46-1.82 (m, 6H) 1.58 (s, 6H) 3.41-3.98 (m, 2H) 4.63 ( dd, J = 2.54, 6.50 Hz, 1H) 6.26 (s, 1H) 7.20-7.29 (m, 1H) 7.51 (br, 1H) 7.52 (br, 1H) 8.28 (d, J = 8.06 Hz, 1H) ^13C -NMR (CDCl _3); 20.88,24.81,27.18,27.71,32.08,64.62,77.20,95.88,
105.97,117.96,123.34,124.84,125.52,131.71,139.35,1
56.48,178,92 ^{IR (KBr); 3320,1734,1647,1601,1551,1516cm -1 1} H-NMR (CDCl 3) δppm; 1.84 (s, 3H) 2.06-2.10 (m, 2H) 2.84 (t, J = 7.81Hz , 2H) 4.06 (t, J = 6.34 Hz, 2H) 6.26 (s, 1H) 7.36 (dd, J = 7.08, 7.79 Hz, 1H) 7.58 (ddd, J = 1.46, 7.08, 8.19 Hz, 1H) 7.77 ( d, J = 7.79Hz, 1H) 8.33 (dd, J = 1.22,8.19Hz, 1H) 13.09 (br, 1H) 13 C-NMR (CDCl 3); 20.66,27.88,30.66,63.13,107.96,118.63,123.65 , 12
4.74,124.92,131.86,140.70,154.22,170.87,178.70 ^{IR (KBr); 3298,1729,1647,1599,1545cm -1 1} H-NMR (CDCl 3) δppm; 2.06 (m, 2H) 2.32 (t, J = 7.84Hz, 2H) 2.78 (t, J = 7.75 Hz, 2H) 3.56 (s, 3H) 6.24 (s, 1H) 7.31 (dd, J = 7.15, 8.14Hz, 1H) 7.56 (ddd, J = 1.28, 7.15, 8.34Hz, 1H) 7.75 (brd, J = 8.14 Hz, 1 H) 8.31 (dd, J = 1.28, 8.34 Hz, 1 H) 12.77 (br, 1 H) ¹³ C-NMR (CDCl ₃ ); 24.08, 32.92, 33.22, 51.58, 108.18, 118.63, 123.67, 124.78, 125.04 , 131.86,140.66,154.18,173.28,1
78.73

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Claims (1)

(57) [Claims] (1) General formula [Wherein, R ¹ is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a hydroxyl group, a protected hydroxyl group, a nitro group, a halogen atom, a cyano group, an amino group, an ester group, and a substituted ester group. A lower alkyl group, a linear or branched alkyl group having 1 to 4 carbon atoms having 1 to 2 carbon atoms;
It represents an individually substituted lower alkylamino group, lower alkoxy group or 5- or 6-membered nitrogen-containing heterocyclic group which may have a substituent, and each R ¹ may be different from each other. X
Represents a halogen atom. Formula CH≡C-R ² [wherein, R ² an aniline derivative represented by] a hydrogen atom, a lower alkyl group, lower alkenyl group, a cycloalkyl group, a hydroxyl group, protected hydroxyl group, a nitro group, a halogen atom , A cyano group, an amino group, an ester group, a lower alkyl group substituted with an ester group, a linear or branched alkyl group having 1 to 4 carbon atoms is 1 to 2 or less.
It represents an individually substituted lower alkylamino group, lower alkoxy group or 5- or 6-membered nitrogen-containing heterocyclic group which may have a substituent. Carbonylation with carbon monoxide using a palladium catalyst in the presence of an acetylene derivative represented by the general formula: [Wherein, R ¹ and R ² are the same as above. A method for producing a 4-quinolone derivative represented by the following formula: