JPH0375541B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 6,7-dihydro-9-fluoro-5
-Methyl-1-oxo-1H,5H-benzo[ij]
The present invention relates to an intermediate for producing quinolidine-2-carboxylic acid (flumequin).

The flumequin is a known antimicrobial compound,
As described in U.S. Pat. No. 3,896,131 (Example 3),
and has been complained about. The starting material for the process described in this patent is 6-fluoro-2-
Methyl-tetrahydroquinoline (6-fluorotetrahydroquinaldine). 6-Fluorotetrahydroquinaldine was first manufactured by Mirek.
(Chem. Abs., 62 5252, 1965) from the compound 6-fluoroquinaldine by conventional chemical or catalytic reduction treatments.
The Mirek method for preparing 6-fluoroquinaldine involves treatment of 4-fluoroaniline with concentrated acid, zinc chloride, and paraldehyde.
The mixture is left at ambient temperature for 2 hours, then boiled, made alkaline and steam distilled. The distillate is extracted with benzene, dried and the solvent is removed. The residue is vacuum distilled and dissolved in concentrated aqueous hydrochloric acid. The solution is treated with zinc chloride in hydrochloric acid and cooled. The precipitate was washed with cold hydrochloric acid, dissolved in concentrated sodium hydroxide, and steam distilled to give 6-
Obtain fluoroquinaldine. 6 in the Mirek method
-The yield of fluoroquinaldine is reported to be only 36.9%. To produce flumequin, 6-fluoroquinaldine is reduced to 6-
In the case of fluorotetrahydroquinaldine, even a further reduction in overall yield results.

The intermediates of the present invention represent a significant improvement over prior art flumequin production methods. By using this intermediate, extremely high yields of 6-fluorotetrahydroquinaldine of 70-80% can be obtained. Additionally, the use of this intermediate offers various practical advantages, including a reduction in the number of reaction reagents and a reduction in the number and difficulty of work steps in the production of flumequin.

The present invention is based on the formula (): 6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid (flumequin)
The purpose of the present invention is to provide an intermediate used in the manufacture of (wherein R is hydrogen or an alkyl group having 1, 2 or 3 carbon atoms).

This intermediate or its acid addition salt is generally produced by the following method. That is, crotonaldehyde or a precursor of crotonaldehyde, such as acetaldehyde, acetal or paraldehyde, which produces crotonaldehyde under the acidic conditions of the reaction, and 4-fluoroaniline, if necessary in an alcoholic solution, are mixed in a dilute solution such as hydrochloric acid. It is produced by reaction in the presence of aqueous acid at a temperature within the range of about 50-60°C.

Furthermore, using the intermediate represented by the above formula (), flumequin is produced as follows.

(a) heating the above intermediate to obtain a mixture of 6-fluoroquinaldine and 6-fluorotetrahydroquinaldine as acid salts; (b) treating the acid salts with a base in the presence of an acid; The mixture is then reduced to give 6-fluorotetrahydroquinaldine, optionally purified, as an acid salt, (c) a dialkyl alkoxy methylene malonate such as diethyl ester, where the alkyl has 1 to 3 carbon atoms. ) to form a compound: (d) cyclization by heating in the presence of polyphosphoric acid followed by saponification to obtain flumequin.

The novel intermediate of the present invention is a compound of the above formula (), in which R is hydrogen or a methyl group, and the compound as a hydrochloride is particularly preferred.

When preparing the intermediates of the invention, a slight, e.g. 5 mol % excess of crotonaldehyde in an aqueous alcoholic solution (preferably an aqueous methanolic solution)
is preferably added to the mixture of 4-fluoroaniline and dilute hydrochloric acid. It is also possible to use paraldehyde, but both the yield and the purity of the product are inferior. Other reaction reagents such as acetaldehyde, acetal, etc., which are precursors to crotonaldehyde under the acidic conditions of the reaction, can also be used. Although pure crotonaldehyde or an aqueous solution (eg, 85%) of crotonaldehyde can be used, an aqueous alcoholic solution is preferred to maintain reaction homogeneity and increase yield. The ratio of methanol to 85% crotonaldehyde solution is approximately 1
ml/g. The rate of aldehyde addition appears to have some effect on yield. Better yields of product are achieved with slower addition rates. The rate of addition is somewhat easily controlled using crotonaldehyde solution. In a 40 molar scale operation, the addition is desirably carried out over a period of about 8 hours at a temperature of about 50-60°C, preferably about 55°C.
Careful temperature control is important, as significant deviations from this temperature range will result in reduced yields.

Dilute hydrochloric acid, eg 2-6N, preferably about 4N, gives the best yields. The amount of hydrochloric acid used is approximately 0.5 per mole of 4-fluoroaniline. Other strong acids such as sulfuric or phosphoric acid can also be used.

In step (a) of the above reaction, the intermediate from the previous step is optionally filtered to remove any solid contaminants and then heated to reflux to separate the intermediate from 6-fluoroquinaldine and 6-fluoroquinaldine. Converted to a mixture with tetrahydroquinaldine. A currently preferred method of carrying out the heating step involves slowly adding the filtrate to refluxing toluene and azeotroping the water from the reaction mixture. The product is thus obtained as a hydrochloride solid, which can be easily collected, for example by filtration, and then air-dried. Although other azeotropes such as water-acetic acid having a boiling point in the range of about 90-120°C can be used, toluene is preferred because a solid product is formed.

Alternatively, the intermediate can be heated under reflux conditions, or toluene can be added and then refluxed. After removing the organic phase, the resulting mixture is basified and extracted (e.g. with toluene),
Isolate by drying and precipitating as a salt by adding acid (eg by bubbling gaseous HCl). If necessary, after extraction and drying, remove the solvent (e.g. toluene) under vacuum.
is removed, a second solvent (eg acetone) is added, and the product is collected as a salt which precipitates out by adding an acid.

In step (b) for reduction, the dry solid is mixed with isopropanol (approximately 1 ml/g) and acetic acid (approximately 1.0 ml/g).
ml/g) and treated with a slight molar excess of base, such as ammonium acetate or triethylamine.

The mixture is cooled and the solid residue (ammonium chloride or triethylamine hydrochloride) is removed, for example by filtration. This filtrate was loaded with carbon.
A platinum-based reduction catalyst, such as % platinum, is added at about 10-20 g/mol and the mixture is
Under pressure of 2.109~4.921Kg/ ^cm2 (approximately 30~70psi),
Hydrogenate at a temperature of 15°C or lower. The progress of the reaction can be easily monitored by chromatographic analysis. After the reaction is complete, the catalyst as well as other residual solids are removed by filtration. The solvent is removed by evaporation and the residue is dissolved in a suitable solvent such as isopropanol. This solution is treated with an anhydrous acid such as hydrogen chloride to precipitate 6-fluorotetrahydroquinaldine as an acid salt. The overall yield is typically 70-85% for this first product. Additional product was obtained by concentrating the isopropanol solution, increasing the yield to 5-10%.
increase

After further reduction, filtration and evaporation, the product is isolated as the free base, for example by suspending it in water and neutralizing it with a weak base such as aqueous ammonia. Extraction (e.g. with toluene)
6-fluorotetrahydroquinaldine is obtained by subsequent drying and evaporation. If necessary, the product is further purified by vacuum distillation.

In step (c), the condensation of 6-fluorotetrahydroquinaldine and a dialkyl diester of ethoxymethylene malonate such as diethyl ester is carried out without a solvent at 100 to 200°C for about 1 to 5 hours or This is done by allowing it to act until it is completed. The reaction product is an oil and does not need to be isolated or purified.

To carry out step (d), polyphosphoric acid is added to the oily product from step (c) and this solution (optionally diluted with toluene) is heated at 100-140°C to produce flumequin crystallize into an ester of The ester is hydrolyzed to the free base by adding water and heating to reflux under acidic conditions. The isolation and purification of flumequin can be completed, for example, by separating the solid product by filtration, then dissolving it in sodium hydroxide solution and precipitating it with hydrochloric acid. The free base is optionally recrystallized from N,N-dimethylformamide.

The invention is further illustrated by the following non-limiting examples.

Example 1 To a 10 gallon glass-lined Pfaudler reactor was added 20 4N hydrochloric acid followed by 4-fluoroaniline (4444.8 g, 40 moles). The mixture was heated to 55 °C and crotonaldehyde (85% aqueous solution) in methanol (3) was added.
3463.3 g, 42 mol) was added over 8 hours. After the addition was complete, the mixture was cooled to 20°C and stirred overnight (in this mixture, 6
-fluoro-4-hydroxytetrahydroquinaldine had a mp of 128-130°C). The aqueous solution was pressure filtered through a 10 micron string filter and the filter was washed with 2 portions of water. The total volume of solution was approximately 3. The reactor was washed with water and acetone and dried with nitrogen. Toluene (20
) was added to the reactor and refluxed (111°C). The aqueous solution was slowly added to the refluxing toluene and the water obtained by azeotropy was collected. Total addition time is 5.7
It was time. The pot temperature was reduced to 85°C and maintained at this temperature for the first 6.7 hours of azeotropy. After this time, the mixture was cooled to 20°C and stirred overnight. The next morning, a solid precipitate was observed in the reaction vessel. The azeotrope continued. After 4.5 hours, increase pot temperature from 87℃ to 100℃
gradually increased to. After an additional 0.5 hour, the pot temperature was held constant at 111°C, with no observable azeotrope formation. After an additional 0.5 hour, the reaction mixture was cooled to 25°C.

This solid was collected by filtration and toluene (approximately 11
). This solid was placed on a Buchner funnel.
Suction drying for 22 hours and then air drying for a further 42 hours gave 7535 g (93.5%) of a slightly brown solid. This solid was introduced into a dry 10 gallon reactor and further charged with isopropanol (8) and acetic acid (6). The mixture was stirred and heated to 70°C, then ammonium acetate (3084g, 40mol)
was added. The mixture was stirred at 70-75°C for 15 minutes, cooled to 20°C for 0.5 hours and filtered. The reactor and filter cake were washed with isopropanol (4). The resulting white solid was air-dried to yield ammonium chloride (1904.7 based on added ammonium acetate).
g, 89% recovery). The solution was then hydrogenated using 5% platinum on carbon (640 g, 50% w/w) in a clean, dry 10 gallon reactor. The temperature was kept at 15°C and the hydrogen was kept at 3.515°C until the hydrogen uptake was completed (approximately 20 hours).
Kg/cm ² (50psi) was applied.

The reaction mixture was filtered (3 micron string filter) and washed with isopropanol (~4). This solution was reintroduced into the cleaned 10 gallon reactor and vacuumed [70°C, 69.85 cm (27.5 in)].
The solvent was removed under vacuum]. The resulting dark oil was redissolved in isopropanol (8) and the solvent was removed under vacuum to remove residual acetic acid. Cool the residue to 20 °C and add isopropanol (10)
and stirred overnight. This filtered solution was then gradually added to a solution of hydrogen chloride gas (1.75 Kg, 48 mol) in isopropanol (16) (21/2
over time). The resulting slurry was heated to 12°C.
Cool, filter, and dilute with cold isopropanol.
Washed twice (4 and 2 times, respectively). The off-white solid was dried under vacuum (27 inches) at 65° C. for 24 hours to yield 6-fluorotetrahydroquinaldine hydrochloride (5857.5 g, 72.7%). m.
p. was 225-226°C.

The mother liquor was concentrated under vacuum, redissolved in 2 warm isopropanol, cooled overnight and the mixture was filtered. The resulting dark solid was stirred with 1 portion of hot isopropanol, cooled, filtered, and washed with isopropanol. The resulting off-white solid was dried to yield 6-fluorotetrahydroquinaldine hydrochloride (254.0 g, 3.2%).

The resulting mother liquor was concentrated in vacuo to give 1380 g of a dark oil. Analysis shows that this thing accounts for about 14%.
That is, it was found to be 193 g of product. This gave an additional 2.5% product.

Example 2 Crotonaldehyde (93%,
79.13g, 1.05mol) in 4N hydrochloric acid (500ml)
Added to a solution of fluoroaniline (111.12g, 1 mole) at 55°C±5 over 31/2 hours.
After this addition is complete, add toluene (400ml) and
The mixture was heated under reflux for 4 hours. The mixture was cooled and the organic phase was removed. The aqueous layer was made basic to pH 11 with 50% sodium hydroxide solution (100 ml),
The free base was extracted twice with toluene (each with 400
ml and 200ml). The combined toluene extracts were washed with water (300 ml), and the toluene solution was dried by azeotropic distillation. Toluene was removed by distillation, acetone (300ml) was added and the solution was cooled to below 20°C. This solution was treated with hydrogen chloride (36g) and the temperature was kept below 35°C until the solution became acidic. After cooling the suspension at 0°C for 2 hours, the product was collected, washed with acetone (200 ml) and dried under vacuum.
Drying at 35°C gave a slightly brown solid. A mixture of hydrochloride salts was isolated in 82% yield.

The hydrochloride mixture was suspended in acetic acid (50ml) and isopropanol (100ml) and heated with ammonium acetate at 60°C for 10 minutes. Precipitated ammonium chloride was removed by filtration and washed with isopropanol (25 ml). The filtrate was hydrogenated in the presence of 5% palladium on carbon (50% water, ² g) under an initial pressure of 60 psi.

The reaction was completed in 8-12 hours. remove the catalyst,
Isopropanol in the filtrate was removed by evaporation.

Water (200ml) was added with cooling and the solution was made basic to PH9 with ammonia solution (50ml).
The cooled solution was diluted twice with toluene (200 ml and 100 ml, respectively).
ml) and the combined organic layers were washed with water (300 ml). Finally, the toluene solution was dried by azeotropic distillation and the toluene was removed by evaporation under reduced pressure to yield a dark brown oil that crystallized on standing. The yield was about 93% for 6-fluorotetrahydroquinaldine. The overall yield was 76%. Also mp is 35~
It was 40℃.

Example 3 6-fluorotetrahydroquinaldine (12.05
Kg, containing 10% toluene) and diethyl ethoxymethylene malonate (16.2 Kg), 225
Fill the Pfödler reactor and place under vacuum for 4 hours.
Heated at 125°C. Ethanol (3.1Kg) was recovered. The product was cooled, diluted with toluene (35) and tetraphosphoric acid (35Kg), heated again to reflux for 2 hours, cooled to 80°C, diluted with water (128) and refluxed for 6 hours. The hydrolysis was completed. The crude flumequin was collected and the free acid was washed acid-free with water and then with methanol. The wet cake was dissolved in sodium hydroxide solution (2.94Kg/59), heated and filtered through a cartridge filter heated to 90°C, and acidified with hydrochloric acid (6.64). The product was collected and washed with water to make it acid-free.
Washed with methanol and dried in a vacuum oven. The yield of flumequin was 15.4Kg (90.8%). The dry solid was dissolved in N,N-dimethylformamide (70) at 125°C and cooled to 100°C with stirring, then cooled to 7°C with cold water. collect the product,
Washed with methanol and dried as before. Overall, the yield of flumequin after recrystallization was 14.4
kg (82.3%). This one is mp253~255
It was warm at ℃.

Example 4 A mixture of 606 Kg of diethyl ethoxymethylene malonate and 400 Kg of 6-fluorotetrahydroquinaldine was stirred and heated at about 125°C for 5 hours. The mixture was cooled to about 95°C and evaporated.

To this stirred reaction mixture was added 450 g of toluene,
Next, 908Kg of polyphosphoric acid was added at a reaction temperature of 90 to 100℃.
was added at a rate such that The mixture was then heated to reflux for 14 hours.

To this mixture was added 950 g of water over a period of 5 hours. The ester was saponified by heating at 110-115° C. for 13 hours while removing toluene as a toluene-water azeotrope. Flumequin as a solid product was separated by filtration and washed three times with warm water and then with N,N-dimethylformamide.
Recrystallization from N,N-dimethylformamide gave flumequin as a white solid.

Further, the water-washed flumequin was treated with ammonium hydroxide to dissolve, decolorize, filter, and then precipitate with concentrated hydrochloric acid. Flumequin was obtained as a white solid by recrystallization. mp253~255℃.

Claims (1)

[Claims] 1. General formula (wherein R is hydrogen or an alkyl group having 1, 2 or 3 carbon atoms) and acid addition salts thereof. 2. The compound according to claim 1, wherein R is hydrogen. 3. A compound according to claim 1, wherein R is methyl. 4 6-Fluoro- according to claim 2
4-Hydroxytetrahydroquinaldine hydrochloride. 5 6-fluoro-4 according to claim 3
-Methoxytetrahydroquinaldine hydrochloride.