JPH0215066A - Intermediate for producing flumequine - Google Patents

Abstract

NEW MATERIAL: A compd. represented by formula I (wherein R is H or 1-3C alkyl) and its acid adducts.

EXAMPLE: 6-fluoro-4-hydroxytetrahydroquinaldine hydrochloride.

USE: An intermediate for producing 6,7-dihydro-9-fluoro-5-methyl1-oxo-1H,5H- benzo[ij] quinolidine-2-carboxylic acid (represented by formula II). Yield is enhanced by using this intermediate and advantages such as the conservation of the number of reaction reagents from an aspect of production, the number of work processes and the reduction of dfficulty are shown.

PROCESS: Crotonaldehyde or a crotonaldehyde precursor such as acetaldehyde or para-aldehyde forming croton aldehyde under an acidic reaction condition and 4-fluoroanilln are reacted in the presence of dilute aq. acid such as hydrochloric acid to obtain the compd. represented by formula I.

COPYRIGHT: (C)1990,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 6,7-sihydro-9-fluoro-5methyl-
The present invention relates to an intermediate for producing 1-oxo-IH,5F Ehenzo[ij]quinolidine-2-carboxylic acid (Flumequin).

Flumequin is a known antimicrobial compound and is described and claimed in US Pat. No. 3,896,131 (Example 3). The starting material for the process described in this patent is 6-fluoro2-methyl-tetrahydroquinoline (6-fluorotetrahydroquinaldine). 6-Fluorotetrahydroquinaldine was first developed by Mirek (Chem, 8 bs., 625).
252.1965) from the compound 6-fluoroquinaldine by conventional chemical or catalytic reduction treatments. The Mirek method for preparing 6-fluoroquinaldine consists of a concentrated acid of 4-fluoroaniline,
Includes treatment with zinc chloride and valaldehyde. The mixture is left at ambient temperature for 2 hours, then boiled, made alkaline and thin-gas 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 is washed with cold hydrochloric acid, dissolved in concentrated hydroxide, and steam distilled to give 6-fluoroquinaldine. It has been reported that the yield of 6-fluoroquinaldine in the Mirek method is only 36.9%. Reduction of 6-fluoroquinaldine to 6-fluorotetrahydroquinaldine to produce flumequin even results in a further reduction in overall yield.

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% are 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 provides a compound having 2 (■): 6,7-sihydro-9-fluoro-5
-Methyl-1-oxo-IH,5H-benzo(ij)quinolidine-2-carboxylic acid flumequin), which intermediate has the general formula: (wherein R is hydrogen or an alkyl group having 1, 2 or 3 carbon atoms).

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

Furthermore, using the intermediate represented by the above formula (II),
The production of flumequin is carried out 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 a weak acid, and then The mixture is reduced to give 6-fluorotetrahydroquinaldine, optionally purified, as an acid salt, and (C) dialkyl alkoxymethylene malone-1-, such as diethyl ester (where alkyl is 1 to 3 carbon atoms) (1) consisting of cyclization by heating in the presence of poly'AH and then saponification to obtain flumequin.

The novel intermediate of the present invention is a compound of the above formula (n), 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, aqueous methanol solution) is 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 me/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 implementation, the addition desirably ranges from about 50 to 60°C, preferably about 55°C.
It is carried out for about 8 hours at a temperature of °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 m2 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;
The intermediate is then heated to reflux to convert the intermediate to a mixture of 6-fluoroquinaldine and 6-fluorotetrahydroquinaldine. 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.

It is also possible to use other azeotropes such as water-acetic acid having a boiling point in the range of about 90 to l20'C, but 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), drying and precipitation as a salt by addition of acid (e.g. by bubbling gaseous HCβ). 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.

For the reduction (in the BL step), the dry solid was mixed with isopropanol (about 1 ml/g) and acetic acid (about 1.0 m7!).
/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. Approximately 10 to 20 g of carbon-supported 5g (1 mol) was added to this filtrate, and the final stage was heated to approximately 2.5 g. l O9~4.92
Under a pressure of Ikg/c+i (approximately 30-70psi), 1
Hydrogenate at a temperature of 5°C or lower. The progress of the reaction can be determined by chromatography using CL. ) i'l; J
It can be easily monitored by JT. After the reaction is completed, j“
111 Jr. and other residual solids are removed by filtration. The solvent is removed once 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 is obtained by concentrating the isopropanol solution, increasing the yield by 5-10%.

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 (eg with toluene) followed by drying and evaporation yields 6-fluorotetrahydroquinaldine. 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.

(d) To carry out the step, polyphosphoric acid (to the oily product from step C1) is added and this solution (optionally diluted with toluene) is heated at 100-140'C to produce flumequin This 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 4N hydrochloric acid 2ON followed by 4-fluoroaniline (4,444.8 g, 40 moles). The mixture was heated to 55°C and crotonaldehyde (85% aqueous solution 3e) in methanol (3e) was added.
, 463.3 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 +n, p of 6-fluoro-4-hydroxytetrahydroquinaldine as isolated).
, was 128-130°C). The water-repellent mixture was pressure filtered through a 10 micron string filter, and the filter was washed with 21 g of water. The total volume of solution was approximately 31 ff. The reactor was washed with water and acetone and dried with nitrogen. 20 l of toluene 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 was 5.7 hours.

Reduce the pot temperature to 85°C for the first 6.7 hours of azeotropy.
This temperature was maintained. 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, the pot temperature was gradually increased from 87°C to 100°C. After another 0.5 hours, the pot temperature was increased to 111℃.
was held constant, but there was 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 washed with toluene (ca. 111). This solid was suction dried on a Buchner funnel for 22 hours and then air dried for a further 42 hours, yielding 7,535 g (93.5%) of a slightly brown solid. This solid was introduced into a dry 10 gallon reactor and charged with isopropanol (8β) and acetic acid (6β). The mixture was stirred and heated to 70°C, then treated with ammonium acetate,
(3,084 g, 40 mol) was added. 7 of the mixture
Stir at 0-75°C for 15 minutes, cool to 20°C for 0.5 hour, and filter. The reactor and filter cake were washed with isopropanol (47%). The resulting white solid was air-dried to yield ammonium chloride (1,904.7 g based on added ammonium acetate, 89% recovered). Solution. and then 5% platinum supported on carbon (640 g, 50% w/w) in a clean, dry 10 gallon reactor.
) was used for hydrogenation. The temperature was maintained at 15°C, and hydrogen was added until hydrogen uptake was completed (approximately 20 hours).
It was applied at 3.515 Kg/cnl (50 psi).

Filter the reaction mixture (3 micron string filter)
and washed with isopropanol (approx. 41 g). This solution was reintroduced into the cleaned 10 gallon reactor and vacuum (7
The solvent was removed under 0°C, 69.85 cm (27,5 inches) vacuum. The resulting dark oil was redissolved in isopropanol (81) and the solvent was removed under vacuum to remove residual acetic acid. The residue was cooled to 20° C., dissolved in isopropanol (10N) and stirred overnight. This filtered solution was then gradually added to isopropanol (16
(2V over 2 hours) to a solution of hydrogen chloride gas (1.75Kg, 48mol) in p). The resulting slurry was cooled to 12°C, filtered, and washed twice (41 and 21 times, respectively) with cold isopropanol.

The off-white solid was incubated at 65°C for 24 hours under vacuum (68°C).
, 58 cm (2 ft.)] to give 6-fluorotetrahydroquinaldine hydrochloride (5,857.5 g,
72.7%). m, p, were 225-226°C.

The mother liquor was concentrated under vacuum, redissolved in 2β hot isopropanol, cooled overnight and the mixture was filtered. The resulting dark solid was stirred with 11 portions 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 is about 14%, or 19
It turned out to be 3g of product.

This gave an additional 2.5% product.

Example 2 Crotonaldehyde in methanol (93%, 79,1
3 g, 1.05 mol) was added to a solution of 4-fluoroaniline (111.12 g, 1 mol) in 4N hydrochloric acid (500 mj) at 55°C ± 5 at 3V over 2 hours.

After this addition is complete, add toluene (400 mj2) and
The mixture was heated under reflux for 4 hours.

The mixture was cooled and the organic phase was removed. 5 aqueous layer
The base was made basic to pH 1 with 0% sodium hydroxide solution <100 mJ, and the liberated base was extracted twice with toluene (400 ml and 200 ml, respectively).The combined toluene extracts were washed with water (300 mA), and the toluene solution was dried by azeotropic distillation. The toluene was removed by distillation, acetone (300 n+) was added, and the solution was cooled to below 20°C. The solution was treated with hydrogen chloride (36 g),
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 (200m6) and dried under vacuum at 35°C to give a slightly brown solid. Yield 8 of a mixture of hydrochloride salts
Isolated at 2%.

The hydrochloride mixture was suspended in acetic acid (50 mjl') and isopropanol (100 mf) and heated with ammonium acetate at 60°C for 10 minutes.

The precipitated ammonium chloride was removed by filtration and washed with isopropanol (25 mf). The filtrate was incubated at an initial pressure of 4.218 Kg/cIA (60 psi) in the presence of 5% palladium on carbon (50% moisture, 2 g).
Hydrogenated under

The reaction was completed in 8-12 hours. The catalyst was removed and the isopropanol in the filtrate was removed by evaporation.

Water (200 ml was added with cooling and the solution was made basic to p119 with ammonia solution (50 mA). The cooled solution was diluted twice with toluene (200 mj2 and 10
A 0 ml portion was extracted 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%.

Further, m and p were 35 to 40°C.

Example 3 6-fluorotetrahydroquinaldine (12,05Kg
, containing 10% toluene) and diethyl ethoxymethylene malonate (16°2 Kg) were charged to a 2251 Pfd. reactor and heated at 125° C. for 4 hours under vacuum. Ethanol (3.1 Kg) was recovered. The product was cooled and mixed with toluene (351) and tetraphosphoric acid (3
5Kg) and heated again to reflux for 2 hours,
It was cooled to 80°C, diluted with water (128N), and refluxed for 6 hours to complete the hydrolysis. The crude flumequin was collected and the free acid was washed acid-free with water and then with methanol. The wet cake was soaked in sodium hydroxide solution (2,
94Kg/59β), heated and filtered through a cartridge filter heated to 90°C, and dissolved in hydrochloric acid (6,64
ff) to make it acidic. The product was collected, washed acid free with water, methanol and dried in a vacuum oven.

The yield of flumequin was 15.4 Kg (90.8%). The dry solid was dissolved in N,N-dimethylformamide (70
1) at 125°C, cooled to 100°C with stirring, and then cooled to 7°C with cold water. The product was collected, washed with methanol and dried as before. The overall yield of flumequin after recrystallization was 14.4 Kg (
82.3%). This one is m, p, 253~2
The temperature was 55°C.

Example 4 606Kg of diethyl ethoxymethylene malo and 40
The mixture with 0 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 e of toluene followed by 908 h of boIJ ta acid at a reaction temperature of 90-10
Additions were made at a rate such that 0°C was maintained.

The mixture was then heated to reflux for 14 hours.

To this mixture was added 9501 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.

Claims (5)

[Claims] (1) Compounds having the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (where R is hydrogen or an alkyl group having 1, 2 or 3 carbon atoms) and their acid addition salts. (2) The compound according to claim (1), wherein R is hydrogen. (3) The compound according to claim (1), wherein R is methyl. (4) 6-fluoro- according to claim (2)
4-Hydroxytetrahydroquinaldine hydrochloride. (5) 6-fluoro- according to claim (3)
4-Methoxytetrahydroquinaldine hydrochloride.