IE50928B1

IE50928B1 - Substituted tetrahydroquinaldines and their use in the preparation of flumequine

Info

Publication number: IE50928B1
Application number: IE326/81A
Authority: IE
Original assignee: Riker Laboratories Inc
Priority date: 1980-02-19
Filing date: 1981-02-18
Publication date: 1986-08-20
Also published as: GB2069498B; JPH0375541B2; AU524459B2; NZ196293A; JPH0215066A; GB2069498A; IE810326L; JPH0416474B2; JPH0215077A; FR2476079B1; AU6742581A; FR2476079A1

Abstract

Compounds of the formula: wherein R is hydrogen or alkyl having 1-3 carbon atoms, and acid addition salts thereof, are useful intermediates in the preparation of 6- fluorotetrahydroquinaldine and flumequine which has the formula:

Description

This invention relates to an improved process for the preparation of 6,7-dihydro-9-fluoro-5-metbyl-loxo-lH,5H-benzo[i j]quinolizine-2-carboxylic acid (flumequine) and intermediates therefor starting with 4-fluoroaniline.

Flumequine is a known antimicrobial compound described and claimed in United States Patent No. 3,896,131 (Example 3). The starting material for the process described in that patent is 6-fluoro-2-methyl10 tetrahydroquinoline (6-fluorotetrahydroguinaldine). 6-Fluorotetrahydroquinaldine is prepared from 6-fluoroguinaldine, a compound first described by Mirek (Chem.

Abs. 62, 5252, 1965), by routine chemical or catalytic reduction procedures. The Mirek process for preparing 615 fluoroquinaldine involves treating 4-fluoroaniline with concentrated acid, zinc chloride and paraldehyde. The mixture is left at ambient temperature for two hours, followed by boiling, alkalization and steam distillation. The distillate is extracted with benzene, dried and the solvent removed. The residue is distilled in vacuo and dissolved in concentrated hydrochloric acid in water. The solution is treated with zinc chloride in hydrochloric acid and cooled. The precipitate is washed with cold hydrochloric acid, dissociated witn concentrated sodium hydroxide and steam distilled to prepare 6-fluoroquinaldine. The yield of 6-fluoroquinaldine from the Mirek process is reported to be only 36.9%. When the 6-fluoroquinaldine is reduced to 6-fluorotetrahydroquinaldine in order to prepare flumequine an even further reduction in overall yield results.

The process of the present invention is a marked improvement over the prior art process. It results in significantly higher yields of 6-fluorotetrahydroquinaldine in the range of 70 to 80 percent. Furthermore, it offers various practical advantages including a reduction in the number of reagents and the number and difficulty of operational steps.

The present invention provides a process fcr preparing the compound 6,7-dihydro-9-fluoro-5-methyl-loxo-lH,5H-benzolij)quinolizine-2-carboxylic acid (flumeauine) of Formula I Formula I which comprises: a) reacting 4-fluoroaniline with in the presence of dilute aqueous acid such as hydrochloric acid and between 50 and 60°C with a reactant selected from crotonaldehyde, precursors which generate crotonaldehyde under the acidic reaction conditions such as acetaldehyde, acetal or paraldehyde, and alcoholic solutions of crotonaldehyde or such precursor wherein the solvent comprises an alkanol ROH with R being alkyl of one, two or three carbon atoms, to provide a compound of the formula OR wherein R is hydrogen or (when an ROH alcoholic solution is used) alkyl having one, two or three carbon atoms as e.g., the acid addition salts; b) heating the product of step a), in the presence of acid if this step a) product is not in acid salt form, to provide a mixture of 6-fluoroouir.aldine and 6-fluoro509 38 tetrahydroquinaldine as acid salts; c) treating said acid salts with base in the presence of weak acid followed by reducing the mixture to provide 6-fluorotetrahydroguinaldine, optionally purified as the acid salt; d) condensing said 6-fluorotetrahydroguinaldine with a dialkyl alkoxymethylenemalonate (where alkyl has one to three carbon atoms) such as the diethyl ester, to provide a compound of the fonnula tl CH=C(C0R)2 wherein R is alkyl of one to three carbon atoms; e) cyclizing the product of d) by heating in the presence of polyphosphoric acid followed by saponifying to provide flumequine.

The novel intermediates of the invention are the compounds of Formula II, with compounds wherein R is hydrogen or methyl, especially as the hydrochloride salt, being preferred.

The essence of the invention lies in the first two steps of the process which are responsible for the significant increase in overall yield.

In the preferred embodiment of the process, the first step involves adding a slight (e.g. 5% molar, excess of an aqueous alcoholic (preferably aqueous methanolic) solution of crotonaldehyde to a mixture of 4-fluoroaniline and dilute hydrochloric acid. Paraldehyde can be used, but the yields and purity of the product are both poorer. Other reactants (such as acetaldehyde and acetal) which are crotonaldehyde precursors under acidic reaction conditions may also be used. Pure crotonaldehyde or an aqueous solution of crotonaldehyde (e.g.85%) can be used, but an aqueous alcoholic solution is preferred to maintain reaction homogeneity and increase yield. The ratio of methanol to 854 crotonaldehyde solution is about 1 ml per gram.

The rate of additon of the aldehyde appears to have some effect on yield. Slow addition provides better yields of product. The rate of addition is somewhat easier to control using a solution of crotonaldehyde.

In a 40 mole scale run, addition is desirably carried out over about 8 hours at a temperature of between about 50 and 60’C and preferably at about 55°C. Careful control of temperature is very important since significant deviations from this temperature range result in a reduced yield.

It has been found that dilute hydrochloric acid, e.g. 2 to 6N, preferably about 4N, gives the highest yields of product. The amount of hydrochloric acid used is about 0.5 liter per mole of 4-fluoroaniline. Other strong acids such as sulfuric or phosphoric acid may also be used.

In the second step of the reaction, the mixture from step one is optionally filtered to remove any solid contaminants, then heated to reflux to convert the compounds of Formula II to a mixture of 6-fluoroquinaldine and 6-fluorotetrahydroquinaldine. The presently preferred method of carrying out the heating step comprises the slow addition of the filtrate to refluxing toluene and allowing the water to azeotrope out of the reaction mixture, in this way the product is obtained as the solid hydrochloride salts which are easily collected, e.g., by filtration, and air-dried. Other azeotropes having a boiling point between about 90 and 120®C such as water-acetic acid can also be used, but toluene is preferred since a solid product is formed.

Alternatively, the reaction mixture of step one may be heated as is under reflux, or toluene may be added and then the mixture refluxed. The product mixture is then isolated after discarding the organic phase, by basifying, extracting (e.g., with toluene), drying, and precipitating as the salts by adding acid (e.g., by bubbling in gaseous HCl). Optionally, after extraction and drying, the solvent (e.g., toluene) is removed in vacuo, a second solvent (e.g., acetone) is added, and the product precipitated as the salts by adding an acid.

For the reduction of step c), the dry solid is dissolved in a warm solution of isopropanol (about 1 ml per gran) and a weak acid such as acetic acid (about l.C ml per gram) and treated with a slight molar excess of a base such as ammonium acetate or triethylamine.

The mixture is cooled and the solid residue (ammonium chloride or triethylamine hydrochloride) is removed e.g., by filtration. To the filtrate is added a platinum-based reducing catalyst such as 5% platinum on carbon, about 10 to 20 g per mole, and the mixture is hydrogenated at a pressure of 30 to 70 psi at a temperature of 15eC or less. The progress of the reaction is readily monitored by chromatographic analysis. After completion of the reduction, the catalyst and 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. The solution is treated with anhydrous acid such as hydrogen chloride to precipitate 6-fluorotetrahyaroquinaldine as the acid salt. Overall yields are typically 70 to 85% of this first crop. Further product is obtained by concentration of the isopropanol solution to increase the yield by 5 to 10%.

Alternatively, after reduction, filtration and evaporation, the product is isolated as the free base, e.g., by suspending in water and neutralizing with weak base such as aqueous ammonia. Extraction (e.g., with toluene) followed by drying and evaporation provides 6-fluorotetrahydroquinaldine. This product may be further purified by vacuum distillation if desired.

In the fourth step, condensation of 6-fluorotetrahydroquinaldine with a dialkyl diester of ethoxymethylenemalonate such as the diethyl ester is carried out by heating the reactants without solvent at 1OO to 2O0°C for about 1 to 5 hours or until the reaction is complete. The intermediate is an oil which need not be isolated or purified.

To carry out step five, polyphosphoric acid is added to the oil from step four and the solution (optionally diluted with toluene) is heated at 100 to 140* C to effect cyclization to the ester of flumecuine. The ester is hydrolyzed to the free acid by adding water followed by heating at reflux under the acid conditions. The isolation and purification of fluraequine can be completed, e.g., by filtering to separate the solid product, followed by dissolving in sodium hydroxide solution and then precipitation with hydrochloric acid.

Hie free base is optionally recrystallized from Ν,Ν-dimethylformamide.

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

Example 1 To a 10 gallon glass-lined Pfaudler reactor were added 20 liters of· 4N hydrochloric acid, followed by 4-fluoroaniline (4,444.8g, 40 moles). The mixture was heated to 55°C, and crotonaldehyde (3,463.3g 85% aqueous soln., 42 moles) in methanol (3 liters) was added over 8 hrs. After the addition, the mixture was cooled to 20’C and stirred overnight. The aqueous solution was pressure filtered through a 10 micron string filter, which was rinsed with 2 liters of water. Total volume of the solution was about 31 liters. The reactor was rinsed with water and acetone and dried with nitrogen. Toluene (20 liters) was added and brought to reflux (Ill’CJ. The above aqueous solution was slowly added to the refluxing toluene, and the water resulting from the azeotrope was collected. Total time of addition was 5.7 hrs. The pot temperature decreased to 85°C and stayed there curing the first 6.7 hours of a2eotroping. After tnis time, the mixture was cooled to 20°C and stirred overnight. The next morning, a solid precipitate was noted in the reaction vessel. The azeotrope was continued. After 4.5 hrs., pot temperature had slowly risen from 87®C to 100°C. After an additional 0.5 hrs., pot temperature was steady at 111°C and there was no visible azeotrope being formed. After an additional 0.5 hrs., the reaction mixture 50828 was cooled to 25“C.

The solid was collected by filtration and rinsed with toluene (about 11 liters). The 6olid was sucked dry on a Buchner funnel for 22 hrs., followed by air drying an additional 42 hrs., yielding 7,535 g (93.5%, light brown solid. The solid was added to the dried 10 gallon reactor, along with isopropanol (8 liters) and acetic acid (6 liters). The mixture was stirred and heated to 70*C, followed by the addition of ammonium acetate (3,084 g, 40 moles).The mixture was stirred 15 minutes at 70-75C, cooled to 20“C for 0.5 hr., and filtered. The reactor and filter cake were rinsed with isopropanol (4 liters). The white solid was air-dried to give ammonium chloride (1,904.7 g, 89% recovery based on the ammonium acetate added). The solution was then hydrogenated in the clean, dry 10 gallon reactor, using 5% platinum on carbon (640 g, 50% w/w). The temperature was kept at 15’C and hydrogen applied at 50 psi until hydrogen uptake ceased (about 20 hours).

The reaction mixture was filtered (3 micron string filter), and rinsed with isopropanol (about 4 liters). The solution was re-added to the cleaned 10 gallon reactor and the solvent removed in vacuo (70“, 27.5 inches vac). The resulting dark oil was redissolved in isopropanol (8 liters, and the solvent removed in vacuo to remove residual acetic acid. The residue was allowed to cool to 20’C, dissolved in isopropanol (10 liters) and stirred overnight. This filtered solution was then added slowly (over 2-1/2 hrs.) to a solution of hydrogen chloride gas (1.75 kg, 48 moles) in isopropanol (16 liters). The resulting slurry was cooled to 12°C, filtered, and rinsed twice with cold isopropanol (4 liters and 2 liters, respectively). The off-white solid was dried under vacuum (27 in, at 65 for 24 hrs., yielding 6-fluorotetrahydroguinaldine hydrochloride (5,857.5 g, 72.7%).

The mother liquors were concentrated in vacuo, redissolved in 2 liters of hot isopropanol, cooled overnight, and the mixture filtered. The resulting dark solid was stirred with 1 liter of hot isopropanol, cooled, filtered and rinsed with isopropanol. The resulting off-white solid was dried, yielding 6-fluorotetrahydroquinaldine hydrochloride (254.Og, 3.2%).

The resulting mother liquors were concentrated in vacuo to 1,380 g dark oil. Analysis showed this was about 14% product, or 193 g, an additional 2.5% of product.

Example 2 Crotonaldehyde (93%, 79.13g, 1.05 moles) in methanol (75 ml) was added to a solution of 4-fluoroaniline (111.12g, 1 mole) in-4N hydrochloric acid (500 ml) over 3-1/2 hrs., at 55eC * 5 . On completion of the addition, toluene (400 ml) was added, and the mixture was heated under reflux for 4 hrs. The mixture was cooled and the organic phase was discarded. The aqueous layer was basified with 50% sodium hydroxide solution (100 ml), to pH 11 and the liberated bases were extracted twice with toluene (400 ml and 200 ml, respectively). The combined toluene extracts were washed with water (300 ml) and the toluene solution dried by azeotropic distillation.

Toluene was removed by distillation, acetone (300 ml) was added, and the solution was cooled to below 20°C. This solution was treated with hydrogen chloride (36 g), keeping the temperature below 35°C until it was acidic. After cooling the suspension at 0eC for two hours, the product was collected, washed with acetone (200 ml) and dried in vacuo to 35°C to give a light brown solid. The mixture of hydrochlorides was isolated in 82% yield.

The mixture of hydrochlorides was suspended in acetic acid (50 ml, and isopropanol (100 ml) and heated with ammonium acetate (20 g) at 60’C for 10 minutes. The precipitated ammonium chloride was removed by filtration and washed with isopropanol (25 ml). The filtrate was hydrogenated in the presence of 5% platinum cn carbon catalyst (504 damp, 2 g) at an initial pressure of 60 psi.

Reaction was complete in 6-12 hrs. The catalyst was removed and the isopropanol in the filtrate was removed by evaporation.

Hater (200 ml) was added, with cooling, and the solution was basified with ammonia solution (50 ml) to pH 9. The cooled solution was extracted twice with toluene (200 ml and 100 ml, respectively) 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 give a dark brown oil which crystallized upon standing. Yield was about 93% of 6-fluorotetrahydroquinaldine. The yield was 76% overall.

Example 3 6-Fluorotetrahydroouinaldine (12.05 kg containing 10% of toluene) and diethyl ethoxymethylene malonate (16.2 kg) were charged to a 225 liter Pfaudler reactor and heated at 125·0 under vacuum for 4 hours. Ethanol (3.1 kg) was recovered. The product was cooled, diluted with toluene (35 liters) and tetraphosphoric acid (35 kg), reheated to reflux for 2 hours, cooled to 80oC, diluted with water (128 liters) and refluxed for 6 hours to complete the hydrolysis. The crude flumequine was collected, washed acid free with water and rinsed with methanol. The damp cake was dissolved in sodium hydroxide solution (2.94 kg/59 liters) filtered hot through a cartridge filter heated to 90°C and acidified with hydrochloric acid (6.64 liters). The product was collected, washed acid free, rinsed with methanol and dried in a vacuum oven. The yield of flumequine was 15.4 kg (90.8%). The dry solid was dissolved in N,N-dimethylformamide (70 liters) at 125’C, allowed to cool with stirring to 100’C then cooled to 7’C with cold water. The product was collected, washed with methanol and dried as before. The yield of recrystallized flumequine was 14.4 kg (82.3%) overall.

Example 4 A mixture of 606 kg of diethyl ethoxymethylene5 malonate and 400 kg of 6-fluorotetrahydroquinaldine was stirred and heated at about 125°C for 5 hours. The mixture was cooled to about 95aC and evaporated.

To the stirred reaction mixture was added 450 liters of toluene, then 908 kg of polyphosphoric acid at a rate to maintain a reaction temperature of 90 to 100°C. The mixture was then heated at reflux for fourteen hours.

To this mixture was added 950 liters of water over five hours. The ester was saponified by heating for 13 hours at 110 to 115°C while removing the toluene via the toluene-water azeotrope. The solid product flumequine was separated by filtration, washed thrice with hot water, then with Ν,Ν-dimethylformamide. Recrystallization form Ν,Ν-dimethyl-formamide gave white solid flumequine.

Alternatively, the water-washed flumequine was treated with ammonium hydroxide to dissolve it, decolorized, filtered, and then precipitated with concentrated hydrochloric acid. Recrystallization provided white solid flumequine.

Claims

CLAIMS :

1. A compound of the formula OR H wherein R is hydrogen or alkyl having one, two or three carbon atoms , or an acid addition salt thereof.

2. A compound according to claim 1 wherein R is hydrogen.

3. A compound according to claim 1 wherein R is methyl.

4. 6-Fluoro-4-hydroxytetrahydroquinaldine hydrochloride.

5. 6-Fluoro-4-methoxytetrahydroquinaldine hydrochloride. 50828

6. A process for the preparation of flumequine comprising: a. reacting 4-fluoroaniline in the presence of dilute aqueous acid and between 50 and 60 e C 5 with reactant selected from crotonaldehyde, precursors which generate crotonaldehyde under the acidic reaction conditions, and alcoholic solutions of crotonaldehyde or such precursor wherein the solvent comprises 10 alkanol ROH with R being alkyl of one, two or three carbon atoms, to provide a compound of the formula wherein R is hydrogen or (when an ROH alcoholic 15 solution is used) alkyl having one, two or three carbon atoms; b. heating the product of step a), in the presence of acid if this step a) product is not in acid salt form, to provide a mixture of 2o 6-fluoroquinaldine and 6-fluorotetrahydroguinaldine as acid salts; c. treating said acid salts with base in the presence of weak acid followed by reducing the mixture to provide 6-fluorotetrahydro15 50828 guinaldine; d. condensing said 6-fluorotetrahydroquinaldine with a dialkyl alkoxymethylenemalonate to provide a conpound of the formula CH-C(COR) 2 /a wherein R is alkyl of one to three carbon atoms; cyclizing the product of step d) by heating in the presence of polyphosphoric acid followed by saponifying to provide flumeguine.

7. The process according to claim 6 wherein said reactant in step a) is an alcoholic solution of crotonaldehyde .

8. The process according to claim 7 wherein said 15 reactant in step a) is a methanolic solution of crotonaldehyde and said compound provided is CH; H ' Cil 3

9. The process according to claim 6 wherein said dilute agueous acid in step a) is hydrochloric.

10. The process according to claim 6 wherein said dialkyl alkyloxymethylenemalonate of step d, is diethyl5 ethoxymethylenemalonate.

11. A process for the preparation of 6-fluorotetrahydroguinaldine comprising: a. reacting 4-fluoroaniline in the presence of dilute agueous acid and between 50 and 60 e C with reactant selected from crotonaldehyde, precursors which generate crotonaldehyde under the acidic reaction conditions, and alcoholic solutions of crotonaldehyde or such precursor wherein the solvent comprises alkanol ROH with R being alkyl of one, two or three carbon atoms, to provide a compound of the formula wherein R is hydrogen or (when an ROH alcoholic solution is used) alkyl having one, two or three carbon atoms; b. heating the product of step a) in dilute acid to provide a mixture of 6-fluoroquinaldine and 6-fluorotetrahydroquinaldine as acid salts; c. treating said acid salts with base in the 5 presence of weak acid followed by reducing the mixture to form 6-fluorotetrahydroguinaldine.

12. A process for the preparation of flumequine comprising: a. reacting 4-fluoroaniline in the presence of 10 dilute aqueous acid and between 50 and 60°C with reactant selected from crotonaldehyde, precursors which generate crotonaldehyde under the acidic reaction conditions, and alcoholic solutions of crotonaldehyde or 15 such precursor wherein the solvent comprises alkanol ROH with R being alkyl of one, two or three carbon atoms, to provide a compound of the formula OR CK20 wherein R is hydrogen or (when an ROH alcoholic solution is used) alkyl having one, two or three carbon atoms; 50828 b. heating and removing water from the product of step a), in the presence of acid if this step a) product is not in acid salt form, by slowly adding the product to a refluxing solvent which forms a binary azeotrope with water and has a boiling point between 90° and 120°C to provide a mixture of 6-fluoroquinaldine and 6-fluorotetrahydroquinaldine as acid salts; c. treating said acid salts with base in the presence of weak acid followed by reducing the mixture to provide 6-fluorotetrahydroquinaldine; d. condensing said 6-fluorotetrahydroguinalcine with a dialkyl alkoxymethylenerealonate to provide a compound of the formula ll CH=C(COR) 2 wherein R is alkyl of one to three carbon atoms; e. cyclizing the product of step d) by heating in the presence of polyphospboric acid followea by saponifying to provide flurcequine.

13. The process of claim 12 wherein said solvent in step b) is toluene.

14. A process for the preparation of 6-fluorotetrahydroquinaldine comprising: 5 a. reacting 4-fluoroaniline in the presence of dilute aqueous acid and between 50 and 60°C with reactant selected from crotonaldehyde, precursors which generate crotonaldehyde under the acidic reaction conditions, and 1q alcoholic solutions of crotonaldehyde or such precursor wherein the solvent comprises alkanol ROH with R being alkyl of one, two or three carbon atoms, to provide a compound of the formula OR F I .KF---CH, H J wherein R is hydrogen or (when an ROE alcoholic solution is used) alkyl having one, two or three carbon atoms; b. heating and removing water from the product 20 of step a), in the presence of acid if this step a) product is not in acid salt form, by slowly adding the product to a refluxing solvent which forms a binary azeotrope with water and has a boiling point 5 0 9 28 between 90° and 120°C to provide a mixture of 6-fluoroquinaldine and 6-fluorotetrahydroquinaldine as acid salts; c. treating said acid salts with base in the 5 presence of weak acid followed by reducing the mixture to form 6-fluorotetrahydroquinaldlne.

15. The process according to claim 14 wherein said solvent of step b) is toluene. 10

16. A compound according to claim 1 substantially as hereinbefore described in any one of the Examples.

17. A process for the preparation of flumequine, the process being substantially as hereinbefore described in Example 3 or 4. 15

18. A process for the preparation of 6-fluorotetrahydroquinaldine, or a salt thereof, the process being substantially as hereinbefore described in Example 1 or 2.

19. A process for the preparation of a compound according to claim 1, the process being substantially as

20. Hereinbefore described.