JP2952705B2 - Method for producing quinolone carboxylic acid derivative - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing a quinolone carboxylic acid derivative.

Conventional technology and its problems General formula [In the formula, R ¹ represents a hydrogen atom or a carboxylic acid protecting group. R ²
Is a hydrogen atom, lower alkyl group, lower alkenyl group, cycloalkyl group, hydroxyl group, protected hydroxyl group, nitro group,
A 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 alkyl group; It represents an alkoxy group or a 5- or 6-membered nitrogen-containing heterocyclic group which may have a substituent, and each R ² may be different from each other. X represents a halogen atom. The quinolone carboxylic acid derivative represented by the following formula is an important compound as an antibacterial agent and as an intermediate for synthesizing the antibacterial agent.

As a method for producing the quinolone carboxylic acid derivative represented by the general formula (II), the following method is conventionally known.

(1) A method of thermally cyclizing 3-arylaminomethylidenemalonates at a high temperature [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, 155]
8 (1985)].

However, in the above method (1), generally, 200 ° C.
The above method cannot be applied to a compound which requires a high temperature and has a thermally unstable functional group. In the method (2), it is necessary to use a stoichiometric amount of an expensive reagent,
There are industrial disadvantages.

Means for Solving the Problems An object of the present invention is to provide a method which is free from the drawbacks of the above-mentioned conventional method, is safe, easy to operate, and is industrially advantageous, and has a high yield and high purity in the general formula ( An object of the present invention is to provide a method capable of producing the quinolone carboxylic acid derivative represented by II).

Means for Solving the Problems The present inventors have conducted intensive studies to solve the problems of the above-mentioned conventional methods, and as a result, a 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.

That is, according to the present invention, the quinolone carboxylic acid derivative represented by the general formula (II) is represented by the general formula (I) Wherein R ¹ and R ² are the same as above. X represents a halogen atom. By carbonylation of the enamine derivative represented by the formula, the compound can be produced in a simple operation, without a by-product, with high yield and high purity.

In the present specification, specific examples of the carboxylic acid protecting group include a protective group in organic.
Synthesis (Protective Groups in Organic Synthesi)
s, the various groups described in Chapter 5 (pages 152 to 192) of Theodora W. Greene, hereinafter simply referred to as “literature”, as well as methyl, ethyl, isopropyl, butyl,
Isobutyl group, tert-butyl group, monochloroethyl group,
Monobromoethyl group, trichloroethyl group, benzyl group, p-methylbenzyl group, p-methoxybenzyl group,
Examples thereof include a p-nitrobenzyl group and a diphenylmethyl group.

Examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, and a neopentyl group.

The lower alkenyl group includes a vinyl group, an allyl group,
-Propenyl group, isopropenyl group and the like.

Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

As the hydroxyl-protecting group, see Chapter 2 of the above document (Chapter 10 to 10).
72) can be exemplified.

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 tert-butylamino group, a di-tert-butylamino group, and a tert-butylethylamino group.

As the 5- or 6-membered nitrogen-containing heterocyclic group, And the like, and a group bonded by a ring nitrogen atom or a ring carbon atom can be exemplified. As the substituent in the nitrogen-containing heterocyclic group, a halogen atom, a hydroxyl group, a lower alkoxy group (for example, a methoxy group, an ethoxy group, a propoxy group,
Isopropoxy, butoxy, isobutoxy, tert
-Butoxy group), a nitro group, a cyano group, an amino group, and a linear or branched alkyl group having 1 to 4 carbon atoms.
Two substituted lower alkylamino groups (specifically, methylamino, ethylamino, diethylamino, propylamino, dipropylamino, tert-butylamino, di-tert
-Butylamino, tert-butylethylamino group, etc.), and a linear or branched alkyl group having 1 to 4 carbon atoms is 1 to
3-substituted lower alkylammonium salts (specifically, trimethylammonium, triethylammonium, methyldiethylammonium, triisobutylammonium, tritert-butylammonium, dimethyltert-butylammonium, etc.), an acyl group (specifically, formyl, Acetyl, propionyl, butyryl, isobutyryl, pivaloyl, benzoyl, p-methylbenzoyl,
p-methoxybenzoyl, p-chlorobenzoyl, p-
Nitrobenzoyl group, etc., acyloxy group (specifically, formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy, benzoyloxy, p-methylbenzoyloxy, p-methoxybenzoyloxy, p-chlorobenzoyl Oxy, p-nitrobenzoyl group, etc.). These substituents may have 1 to 5 substituents on the heterocyclic group.

In the present invention, the compound of the general formula (I) used as a starting material includes known compounds. For example, according to the method described in Synthesis, page 215 (1990), the corresponding aniline and β-ketoester or acetylene carboxylic acid are used. It can be easily prepared from esters.

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

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 (tribenzylideneacetylacetone) 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%, preferably, 0.1 to 10 mol%. Examples of the ligand used together with the divalent complex and the zero-valent complex include monodentate such as ordinary triphenylphosphine, tri (o-tolyl) phosphine, tri (p-tolyl) phosphine, and tri (p-methoxyphenyl) phosphine. 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 acetate salts 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 used is not particularly limited, and is appropriately determined depending on 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 a mixed solvent thereof. The reaction is
The reaction is performed in a carbon monoxide atmosphere, and the pressure is 1 to
It is carried out in the range of 200 kg / cm ² , particularly preferably 1 to 70 k
g / 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, 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.

Effects of the Invention According to the present invention, the quinolone carboxylic acid derivative represented by the general formula (II) can be produced with 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 unless it exceeds the gist of the present invention.

Example 1 Compound (Ia) (243 mg, 0.767 mmol), palladium acetate (9.8 mg, 0.043 mmol), triphenylphosphine (43 mg, 0.163 mmol), potassium carbonate (323 mg, 2.3
(3 mmol) of DMF (3 mmol) is reacted at 120 ° C. for 20 hours under carbon monoxide pressure (20 kg / cm ² ). After adding methanol / methylene chloride and filtering, the filtrate is concentrated,
Treat with diazomethane. After concentration, purification by column chromatography gives compound (IIa) (137 mg, 82%).

^{IR (KBr); 3640,1709,1640,1549,1520cm -1 1} H-NMR (DMSO-d 6) δppm; 2.39 (s, 3H) 3.76 (s, 3H) 7.33 (ddd, J = 1.13,6.90, 7.88Hz, 1H) 7.52 (brd, J = 7.88Hz, 1H) 7.67 (ddd, J = 1.44, 6.90, 8.18Hz, 1H) 8.06 (dd, J = 1.48, 8.18Hz, 1H) 11.90 (br, 1H) ¹³ C-NMR; 18.28,51.67,114.38,117.98,123.76,124.57,125.04,1
32.25,139.11,149.34,167.32,173.43 Elemental analysis (as C ₁₂ H ₁₁ NO ₃ ) C H N Theoretical: 66.35% 5.10% 6.45% Actual: 66.22% 5.26% 6.72% Example 2 Compound (Ib) (184 mg, 0.718 mmol), palladium acetate (7.8 mg, 0.035 mmol), triphenylphosphine (38 mg, 0.14 mmol), potassium carbonate (308 mg, 2.23 mmol)
(3 mmol) of DMF (3 mmol) is reacted at 120 ° C. for 20 hours under carbon monoxide pressure (30 kg / cm ² ). After adding methanol / methylene chloride and filtering, the filtrate is concentrated,
The resulting solid was washed with methylene chloride to give compound (IIa) 11
4 mg are obtained. The washing solution is concentrated and then purified by column chromatography to obtain 13.6 mg of the compound (IIa).

Example 3 Compound (Ic) (173 mg, 0.46 mmol), palladium acetate (6.5 mg, 0.029 mmol), triphenylphosphine (26.5 mg, 0.10 mmol), potassium carbonate (216 mg, 1.5 mmol)
(7 mmol) in DMF (3 ml) is reacted at 120 ° C. for 20 hours under carbon monoxide pressure (20 kg / cm ² ). After adding methanol / methylene chloride and filtering, the filtrate is concentrated,
Treat with diazomethane. After concentration, purification by column chromatography gives compound (IIb) (85 mg, 67%).

^{IR (KBr); 3450,1742,1715,1642,1586,1555,1522,1481cm -1 1} H-NMR (DMSO-d 6) δppm; 3.67 (s, 3H) 3.72 (s, 3H) 3.86 (s, 2H) 7.35-7.91 (m, 3H) 8.09 (dd, J = 1.41, 8.05 Hz, 1H) 12.12 (br, 1H) ^13C -NMR; 37.89, 51.62, 52.25 113.97, 118.24, 124.31, 125.12, 125.22, 132.63 , 138.8
8,146.78,166.67,168.60,173.66 Elemental analysis (as C ₁₄ H ₁₃ NO ₅ ) C H N Theoretical: 61.09% 4.76% 5.09% Observed: 61.18% 5.01% 5.41% Example 4 Compound (Id) (257.2 mg, 0.712 mmol), palladium acetate (8.6 mg, 0.038 mmol), triphenylphosphine (35.6 mg, 0.14 mmol), potassium carbonate (303 mg,
(2 mmol) in DMF (3 ml) was reacted at 120 ° C. for 20 hours under carbon monoxide pressure (20 kg / cm ² ). After adding methanol / methylene chloride and filtering, the filtrate is concentrated and treated with diazomethane. After concentration and purification by column chromatography, compound (IIc) (45.5 mg, 24.5
%) Is obtained.

^{IR (KBr); 3440,1741,1734,1622,1607,1557,1533cm -1 1} H-NMR (DMSO-d 6) δppm; 3.77 (s, 3H) 3.95 (s, 3H) 7.39-8.12 (m, 4H) ¹³ C-NMR; 52.25, 53.99, 116.42, 119.70, 125.04, 125.15, 125.69,1
33.43,137.06 139.16,162.05,165.88,174.35 Elemental analysis (as C ₁₃ H ₁₁ NO ₅ ) C H N Theoretical: 59.77% 4.24% 5.36% Actual: 59.43% 4.24% 5.60% Example 5 Compound (Ie) (212.8 mg, 0.695 mmol), palladium acetate (8.2 mg, 0.037 mmol), triphenylphosphine (35 mg, 0.16 mmol), potassium carbonate (296 mg, 2.1
(3 mmol) of DMF (3 mmol) is reacted at 120 ° C. for 20 hours under carbon monoxide pressure (30 kg / cm ² ). After adding methanol / methylene chloride and filtering, the filtrate is concentrated,
Treat with diazomethane. After concentration, purification by column chromatography gives compound (II d) (65 mg, 37%).

^{IR (KBr); 3400,1725,1644,1628,1603,1564,1535,1497cm -1 1} H-NMR (DMSO-d 6) δppm; 2.38 (s, 3H) 3.77 (s, 3H) 7.48 (dd, J = 6.74, 11.08 Hz, 1H) 7.90 (dd, J = 8.73, 10.87 Hz, 1H) 12.67 (br, 1H) ¹³ C-NMR; 18.30, 51.80 106.37 (d, J = 83.45 Hz) 112.44 (d, J = 72.9Hz) 114.10 121.64 (d, J = 16.6Hz) 136.17 (d, J = 42.05Hz) 147.00 (dd, J = 55.5,979.7Hz) 150.09 152.38 (dd, J = 44.7,982.65Hz) 166.86,172.00 analysis (as _{C 12 H 6 F 2 NO 3} ) C H N Calculated: 56.92% 3.58% 5.53% Found: 56.60% 3.68% 5.46% example 6 Compound (If) (220.4 mg, 0.68 mmol), palladium acetate (8.2 mg, 0.037 mmol), triphenylphosphine (36 mg, 0.14 mmol), potassium carbonate (284 mg, 2.0
(6 mmol) in DMF (3 ml) is reacted at 120 ° C. for 20 hours under carbon monoxide pressure (30 kg / cm ² ). After adding methanol / methylene chloride and filtering, the filtrate is concentrated,
Treat with diazomethane. After concentration, purification by column chromatography gives compound (IIe) (138 mg, 75%).

^{IR (KBr); 3436,1725,1640,1589,1555,1520,1479cm -1 1} H-NMR (DMSO-d 6) δppm; 2.38 (s, 3H) 3.75 (s, 3H) 7.69 (d, J = 6.36 Hz, 1H) 7.85 (d, J = 9.50 Hz, 1H) ¹³ C-NMR; 18.95, 51.88 111.19 (d, J = 87.5 Hz) 114.06, 120.87 124.76 (d, J = 22.3 Hz) 124.76 (d, J) 136.82,150.88 153.72 (d, J = 975.4Hz) 167.25,172.07 Elemental analysis (as C ₁₂ H ₉ ClFNO ₃ ) C H N Theoretical: 53.45% 3.36% 5.19% Observed: 53.27% 3.53% 5.07% Example 7 Compound (Ig) (262.8 mg, 0.69 mmol), palladium acetate (8.3 mg, 0.037 mmol), triphenylphosphine (35.8 mg, 0.137 mmol), potassium carbonate (282 mg,
2.04 mmol) in DMF (3 ml) is reacted at 120 ° C. for 20 hours under carbon monoxide pressure (30 kg / cm ² ). After adding methanol / methylene chloride and filtering, the filtrate is concentrated and treated with diazomethane. After concentration and purification by column chromatography, compound (II g) (125 mg, 55%)
Is obtained.

^{IR (KBr); 3460,1742,1715,1638,1613,1562,1524,1477cm -1 1} H-NMR (DMSO-d 6) δppm; 3.66 (s, 3H) 3.72 (s, 3H) 3.86 (s, 2H) 7.73 (d, J = 6.10 Hz, 1H) 7.89 (d, J = 7.82 Hz, 1H) ¹³ C-NMR; 38.09, 51.88, 52.41 111.47 (d, J = 88.7 Hz) 113.81, 120.57, 125.15 125.48 ( d, J = 81.85 Hz) 135.93,147.64 154.12 (d, J = 979.05 Hz) 166.29,168.46,172.35 Elemental analysis (as C ₁₄ H ₁₁ ClFNO ₅ ) C H N Theoretical: 51.32% 3.38% 4.28% Actual value : 51.42% 3.60% 4.10% Example 8 Compound (Ih) (199 mg, 0.65 mmol), palladium acetate (8.8 mg, 0.039 mmol), triphenylphosphine (37.7 mg, 0.14 mmol), potassium carbonate (289 mg, 2.0
(9 mmol) in DMF (3 ml) is reacted at 120 ° C. for 20 hours under carbon monoxide pressure (30 kg / cm ² ). After filtration, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography to obtain compound (II g) (134 mg, 82%).

^{IR (KBr); 3400,1717,1590,1576,1524cm -1 1} H-NMR (DMSO-d 6) δppm; 5.01 (s, 2H) 7.74 (d, J = 6.88Hz, 1H) 7.95 (d, J = 10.2 Hz, 1 H) ¹³ C-NMR; 68.91, 99.52 110.43 (d, J = 84 Hz) 123.10 (d, J = 80.42 Hz) 127.78, 128.60, 149.01 152.97 (d, J = 964.44 Hz) 169.83,171.90,172.35 Example 9 Compound (Ii) (177.8 mg, 0.70 mmol), palladium acetate (7.8 mg, 0.035 mmol), triphenylphosphine (37 mg, 0.14 mmol), potassium carbonate (278 mg, 2.0
(1 mmol) in DMF (3 ml) is reacted at 120 ° C. for 20 hours under carbon monoxide pressure (30 kg / cm ² ). Add methanol / methylene chloride to the reaction solution and filter. The eluate is concentrated under reduced pressure, and the solid is washed with hot methanol to obtain compound (IIh) (36.8 mg). Total (122.5mg, 87%) IR ( KBr); 3460,1748,1630,1589,1549cm -1 1 H-NMR (DMSO-d 6) δppm; 5.26 (s, 1H) 7.45 (ddd, J = 1.16, 6.95,7.91Hz, 1H) 7.61 (brd, J = 7.91Hz, 1H) 7.77 (ddd, J = 1.48,6.95,8.24Hz, 1H) 8.18 (dd, J = 1.16,8.24Hz, 1H) ^13C -NMR ; 65.12,102.12,119.71,124.94,125.88,127.10,133.27,
140.75,151.70,165.04,172.52 Elemental analysis (as C ₁₁ H ₇ NO ₃ ) C H N Theoretical: 65.67% 3.51% 6.96% Actual: 65.58% 3.75% 6.65%

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // C07B 61/00 300 C07B 61/00 300

Claims (1)

(57) [Claims] (1) General formula [In the formula, R ¹ represents a hydrogen atom or a carboxylic acid protecting group. R ²
Is a hydrogen atom, lower alkyl group, lower alkenyl group, cycloalkyl group, hydroxyl group, protected hydroxyl group, nitro group,
A 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 alkyl group; It represents an alkoxy group or a 5- or 6-membered nitrogen-containing heterocyclic group which may have a substituent, and each R ² may be different from each other. X represents a halogen atom. Wherein the enamine derivative represented by the formula is carbonylated with carbon monoxide in the presence of a palladium catalyst. Wherein R ¹ and R ² are the same as above. ] The manufacturing method of the quinolone carboxylic acid derivative represented by these.