JPH0215077A - Production of flumequine - Google Patents

Abstract

PURPOSE: To obtain fulmekin from 6-fluorotetrahydroquinaldine obtained by heating a reaction product of crotonaldehyde and 4fluoroanilin to reduce the same and dialkylalkoxymethylenemalonate.

CONSTITUTION: A reaction reagent selected from crotonaldehyde, a precursor substance (e.g. acetaldehyde) generating crotonaldehyde under an acidic condition and an alcoholic soln. of crotonaldehyde or the precursor substance and 4- fluoroanilin are reacted in the presence of a dilute acid aq. soln. (e.g. 4N hydrochloric acid) at 50-60°C to obtain a compd. represented by formula I. This compd. is heated to be treated with a base in the presence of weak acid and reduced to obtain 6-fluorotetrahydroquinaldine and a compd. represented by formula II obtained by the condensation of this compd. and dialkylalkoxymithylenemalonate is heated and cyclized in the presence of polyphosphoric acid and saponified to obtain the compd. represented by, formula I. Flumekin is an antimicrobial compd.

COPYRIGHT: (C)1990,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 6,7-sihydro-9-fluoro-5methyl-
1-oxo-LH,5H-benzo(ijlquinolidine-
The present invention relates to an improved method for producing 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 paraldehyde. The mixture is left at ambient temperature for 2 hours, then boiled, made alkaline and steam distilled.

The distillate is extracted with benzene, smoked and stripped of solvent. The residue is vacuum distilled and dissolved in concentrated aqueous hydrochloric acid. This solution is treated with zinc chloride in hydrochloric acid and cooled. The precipitate is washed with cold hydrochloric acid, dissolved with concentrated sodium hydroxide, and steam distilled to obtain 1G-fluoroquinaldine.

It has been reported that the yield of 6-fluoroquinaldine in the Mirek method is only 36%. 6-Reducing fluoroquinaldine to punish flumequin
In the case of -fluorotetrahydride quinaldine, even a further reduction in the overall yield is observed.

The method of the present invention is a significant improvement over the methods of the prior art. The powder method provides extremely high 6-fluorotetrahydroquinaldine C yields in the range of 70-80%. Furthermore,
The method offers a number of practical advantages, including a reduction in the number of reaction reagents and a reduction in the number and difficulty of operational steps.

The present invention provides a compound having the formula (■): 6,7-sihydro-9-fluoro-5
-Methyl-1-oxo-IH,5H-henzo(4N quinolidine-2-carboxylic acid (flumequin) A precursor of crotonaldehyde, such as acetaldehyde, acecool or paraldehyde, and 4-fluoroaniline, optionally in an alcoholic solution, to produce
In the presence of a dilute aqueous acid such as hydrochloric acid, approximately 50-60'c
(2) step ( The product of 1) is heated to form 6 as an acid salt.
- obtaining a mixture of fluoroquinaldine and 6-fluorotetrahydroquinaldine; (3) treating the acid salt with a base in the presence of a weak acid; and then reducing the mixture to obtain the required 6-fluorotetrahydroquinaldine; (4) Condensation with a dialkylalkoxymethylene malonate such as diethyl ester (alkyl means having 1 to 3 carbon atoms) to give the compound: CH= C(CDC82CH*) 2 is prepared, (5) cyclized by heating in the presence of polyphosphoric acid,
It then consists of saponification to obtain flumequin.

In the intermediates of the above formula (II) produced in the present invention, R is hydrogen or a methyl group, and the compound as a hydrochloride is particularly preferred.

The essence of the invention lies in the first two steps of the process, which can respond to a significant increase in overall yield. In the first step of a preferred embodiment of the process of the invention, a slight, e.g. 5 mol % excess of an aqueous alcoholic solution (preferably an aqueous methanol solution) of crotonaldehyde is added to a mixture of 4-fluoroaniline and dilute hydrochloric acid. Added. It is possible to use paraldehyde, but both the yield and the purity of the product are poor.

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 an aqueous solution (eg, 85%) of pure rotonaldehyde or 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 nl/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 is desirably at about 50-60°C;
Preferably, it is carried out at a temperature of about 55° C. for about 8 hours. 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 0.51 per mole of 4-fluoroaniline.

Other strong acids such as sulfuric or phosphoric acid can also be used.

In the second step of the reaction, the mixture from the first step is optionally filtered to remove any solid contaminants and then heated to reflux to separate the compound of formula (n) from 6-fluoroquinaldine and 6-fluoroquinaldine. -converted into a mixture with fluorotetrahydroquinaldine. The currently preferred method of carrying out the heating step is to slowly add the filtrate to refluxing toluene;
including azeotroping 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 may be used, toluene is preferred because a solid product is formed.

The reaction mixture of the first step can also be heated under reflux conditions, or toluene can be added and then refluxed. After removal of the organic phase, the resulting mixture is simply basified, extracted (e.g. with toluene), dried and precipitated as a salt by adding acid (e.g. by bubbling gaseous HC). Let go. If necessary, after extraction and drying, remove the solvent (e.g. toluene) under vacuum, add a second solvent (e.g. acetone) and collect the product as a salt which precipitates out by adding acid. .

In the third step for reduction, the dry solids were treated with Improper Tool (approximately 1 ml/g) and acetic acid (approximately 1.0 ml/g).
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 1 mole of platinum-based reduction catalyst, such as 5% platinum supported on carbon, is added to the filtrate, and the mixture is mixed at approximately 2.109 to 4.921 kg/cu.
Hydrogenation is performed under a pressure of t (approximately 30-70 psi) and at a temperature of 15° C. or less. 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.
It is. Additional product is obtained by concentrating the isopropanol solution, increasing the yield by 5-10%.

After further reduction, filtration and one shot, 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 the fourth step, 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 intermediate is an oil and does not need to be isolated or purified.

To carry out the fifth step, polyphosphoric acid is added to the oil from the fourth step and this solution (optionally diluted with 1-toluene) is heated at 100-140°C to form the ester of flumequin. crystallize.

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 A ff1 lo gallon glass-lined Pfaudler reactor was charged with 20 ml of 4N hydrochloric acid followed by 4-fluoroaniline (4,444.8 g, 40 moles). The mixture was heated to 55 °C and crotonaldehyde (85% aqueous solution 3) in methanol (31)
, 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.
, was 128-130'C). 1 of the aqueous solution
Pressure filtration through a 0 micron string filter,
The filter was washed with 21 parts of water. The total volume of the solution is approximately 3
It was 12. The reactor was washed with water and acetone and dried with nitrogen. Add toluene (20J) to the reactor;
The aqueous solution was slowly added to the refluxing toluene and the resulting azeotropic water was collected. The 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 1) 1℃.
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 (approximately 1)j2). 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 further charged with isopropanol (81) and acetic acid (61). The mixture was stirred and heated to 70°C, then ammonium acetate (3,084g, 40mol) 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 (4β). The obtained white solid was air-dried to obtain ammonium chloride (1,904.7 g based on added ammonium acetate, 89% recovered). solution,
Then in a clean, dry 10 gallon reactor, 5% platinum supported on carbon (640 g, 50% w/w
) 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/cut (50 psi).

Filter the reaction mixture (3 micron string filter)
and washed with isopropanol (approximately 4p). This solution was reintroduced into the cleaned 10 gallon reactor and vacuumed [7
0℃, 69.85c+++ (27.5 inches) vacuum]
The solvent was removed at the bottom. 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 (Ion) and stirred overnight.

This filtered solution was then gradually added to isopropanol (1
(2V over 2 hours) to a solution of hydrogen chloride gas (1.75Kg, 48mol) in 6β). The resulting slurry was cooled to 12°C, filtered, and washed twice with cold isopropanol (41 and 2β, respectively).

The off-white solid was incubated at 65°C for 24 hours under vacuum [68
, 58 cm (2 ft.)] to give 6-fluorotetrahydroquinaldine hydrochloride (5,857.5 g, 7 fluorotetrahydroquinaldine hydrochloride).
2.7%). m, p, were 225-226''C.

The mother liquor was concentrated under vacuum, redissolved in 2p of hot isopropanol - cooled overnight and the mixture was filtered. The resulting dark solid was stirred with warm isopropanol from 1), 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 4N hydrochloric acid (1.12 g, 1 mol of 4-fluoroaniline (1) in 500 m7) at 55°C±5 over 3'A hours.

After the addition was complete, toluene (400 mg) was added and the mixture was heated under reflux for 4 hours.

The mixture was cooled and the organic phase was removed. 5 aqueous layer
The mixture was basified to pH 1 with 0% sodium hydroxide solution (100 mA) and the liberated base was extracted twice with toluene (400 mg2 and 200 ml, respectively). The combined toluene extracts were washed with water (300 mf) and the toluene solution was dried by azeotropic distillation. Toluene is removed by distillation,
Acetone (300 n/litre) was added and the solution was cooled to below 20°C. The 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 mg) and dried under vacuum at 35° C. to give a brown solid. A mixture of was isolated in 82% yield.

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

The precipitated ammonium chloride was removed by filtration and washed with isopropanol (25mj2). The filtrate was collected in the presence of 5% palladium on carbon (50% water, 2 g) at an initial pressure of 4.218 Kg/ca! (60psi)
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 mg) was added with cooling and the solution was made basic to pH 9 with ammonia solution (50 mj2). The cooled solution was diluted with toluene twice (20 On/! and 10 On/! respectively).
The combined organic layers were washed with water (300 mg). 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), 2257! The reactor was charged to a pneumatic reactor and heated at 125° C. for 4 hours under vacuum. Ethanol (3, IKg) 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 (1281!”) and refluxed for 6 hours to complete the hydrolysis. The crude flumequin was collected and the free acid was washed with water to make it acid-free, then with methanol. .The wet cake was soaked in sodium hydroxide solution (2
, 94Kg/59#), heat-filtered through a cartridge filter heated to 90°C, and dissolved in hydrochloric acid (6,
64/) 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 dried solid was dissolved in N,N-dimethylformamide (70
ff) at 125°C, cooled to 100°C with stirring, and then cooled to 7°C with cold water. collect the product,
Washed with methanol and dried as above. The overall yield of flumequin after recrystallization was 14.4 Kg.
(82.3%). This one is m, p, 253
The temperature was ~255°C.

Example 4 606Kg of diethyl ethoxymethylene malonate and 4
The mixture with 00Kg of 6-fluorotetrahydroquinaldine was stirred and heated at about 125"C for 5 hours. The mixture was cooled to about 95"C and evaporated.

450 to this stirred reaction mixture! of toluene, then 908 kg of BoIJX 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 950β of water over a period of 5 hours.

The ester was saponified by heating to a toluene-water azeotrope at 1) 0-1) 5"C for 13 hours while removing otoluene. Flumequin as a solid product was separated by filtration and washed with hot water. It was washed three times with water and then with N,N-dimethylformamide. Recrystallization from N,N-dimethylformamide gave flumequin as a white solid.

Claims (7)

[Claims] (1) (a) a reaction reagent selected from the group consisting of crotonaldehyde, a precursor of crotonaldehyde that generates crotonaldehyde under acidic conditions, and an alcoholic solution of crotonaldehyde or the precursor for crotonaldehyde, and 4- fluoroaniline in the presence of a dilute acid aqueous solution at approximately 50-60°C to form the formula: (b) heating the product of step (a) to obtain a mixture of 6-fluoroquinaldine and 6-fluorotetrahydroquinaldine as an acid salt; (c) treating the acid salt with a base in the presence of a weak acid and then reducing the mixture to obtain 6-fluorotetrahydroquinaldine; (d) the 6-fluorotetrahydroquinaldine and dialkylalkoxymethylene (e) cyclize the product of step (d) by heating in the presence of polyphosphoric acid, A method for producing flumequin, comprising: then saponifying it to obtain flumequin. (2) The method according to claim (1), wherein the reaction reagent in step (a) is an alcoholic solution of crotonaldehyde. (3) The reaction reagent in step (a) is a methanolic solution of crotonaldehyde, and the resulting compound is a compound having the formula: ▲ Numerical formula, chemical formula, table, etc. ▼ ) Method described in section. (4) the dilute acid aqueous solution in step (a) is hydrochloric acid;
A method according to claim (1). (5) The method according to claim (1), wherein the dialkyl alkoxy methylene malonate in step (d) is diethyl ethoxy methylene malonate. (6) (a) Dilute 4-fluoroaniline with a reaction reagent selected from crotonaldehyde, a precursor of crotonaldehyde that generates crotonaldehyde under acidic conditions, and an alcoholic solution of crotonaldehyde or a precursor of crotonaldehyde. The reaction is carried out at approximately 50-60°C in the presence of an aqueous acid solution to produce the formula: ▲Mathematical formula, chemical formula, table, etc.▼ Where R is hydrogen or an alkyl group having 1, 2 or 3 carbon atoms. (b) heating and gradually adding said product to a refluxing solvent which forms a binary azeotrope with water and has a boiling point in the range from 90 to 120°C; (c) treating the acid salt with a base in the presence of a weak acid; 6-fluorotetrahydroquinaldine is then obtained by reducing the mixture, and (d) the 6-fluorotetrahydroquinaldine is condensed with dialkyl alkoxymethylene malonate to form the formula: ▲Mathematical formula, chemical formula, table, etc.▼ A method for producing flumequin, comprising: obtaining a compound having the following. (7) The method according to claim (6), wherein the solvent in step (b) is toluene.