IL27590A - Alkyl 7-dialkylamino-4-hydroxyquinoline-3-carboxylates,their preparation and anticoccidial compositions containing them - Google Patents

Description

27590/2 ΤΛ»ΪΙ ns»33 nVno ΤΛ3 o»n»wani onsan Alkyl 7-dialkylaraino~4-hjrciroxyquinoline«- 3-carboxyiates9 their preparation and anticoccidial compositions containing them MERCK s C0.9 Ci 26153 1 The invention pertains to novel organic hetero- 2 cyclic compounds which are esters of quinoline carboxylic 3 acids to methods of preparing such compounds and to com- positions containing them, which compositions are useful in the control of coccidiosis. 6 The compounds of this invention are novel lower- 7 alk l-Jl-hydroxy-quinoline-S-carboxylates having a lower 8 alkyl radical at the 6-position, and a diloweralkylamino 9 radical at the 7-position. Such compounds are highly potent coccidiostats . 11 An object of this invention is to provide a new 12 class of quinoline carboxylates „ A further object is to 3-3 provide a class of loweralkyl 6,7-disubstituted-¾-hydroxy-^ quinoline-3-carboxylates more potent as anticoccidial ^5 agents than those previously described. More specifically !6 the compounds of the invention are loweralkyl-6 > 7-disubsti- 17 tuted-4-hydroxy-quinoline-3-carboxylates where the 6- 18 substituent is loweralkyl of 2-Ί carbons, and the 7-sub- 19 stituent is a diloweralkylamino radical. Another object is provision of a chemical synthesis of these substances by 21 heat-induced cyclization of the anil obtained on reaction 22 of a Sj!l-disubstituted aniline with diloweralkyl alkoxy- 23 methylene malonate. The invention relates further to anti- 24 coccidial compositions containing such substituted quino- 25 lines as an active ingredients either alone or together 26 with one or more other coccidiostats, and to the method of 27 treating coccidiosis with such compositions. 28 The novel compounds of this invention may be 29 represented by the structural formula OH t 1 where R, represents loweralkyl such as methyl, ethyl, 2 propyl or butyl j 3 Rg represents lower alkyl of 2-¾ carbon atoms such as H ethyl, n-propyl, isopropy 1 and n-butylj R represents a diloweralkylamino radical such as 6 dimethy1amino , diethylamino and di-n-propylamino . 7 The invention also contemplates the quaternary salts 8 obtained on reaction of the quinoline I with a loweralkyl 9 halide .

In the preferred compounds of our invention, R^ H is methyl or ethyl, and the substitution at the 6-7 posi- 12 tions is 6-n-prop l-7-diethylamino and 6-n-butyl-7-diethyl- 13 amino. It is this group of substances that possesses the I1» greatest degree and spectrum of anticoccidial activity, although all of the substances represented by Formula I are 16 good coccidiostatso 17 Representative of specific quinoline compounds 18 within the scope of this invention are methyl 6-n-prop l-7- 19 diethylamino-^-hydroxy-quinoline-3-carboxylate , ethyl 6-n- 20 prop 1-7-diethylamino-^-hydroxy-quinoline-3-carboxylate, 21 methyl 6-n-butyl~7-diethylamino-¾-hydroxy-quinoline-3- 22 carboxylate, methyl 6-=-n-prop l-7-dimethylamino-^-hydroxy- 23 quinoline-3-carbox late , and methyl 6-n-propyl-7-di-n- 24 propylamino-i|-hydroxy-quinoline-3-carboxylate .

The quinolates of this invention are synthesized 1 by reacting said aniline with a diloweralkyl loweralkox 2 methylene malonate of the structure 3 R OCHC(COOR3)2 III The immediate reaction product is the anil having the 6 structure 7 In Compounds II, III and IV the symbols R^, Rg and R^ are 8 as previously defined in Formula I. The anil Compound IV 9 is chemically defined as loweralkyl a-carboloweralkoxy-β- 10 (3~R7-i Rg-anilino)-acr late. The ester (IV) is then 11 converted to the loweralkyl -hydroxy-6-Rg-7-R -quinoline- 12 3-carboxylate by heating at elevated temperatures. 13 The reaction of the aniline (II) with the malonate lH ester (III) is preferably carried out in an inert solvent medium such as in a loweralkanol, e.g. methanol, ethanol ID or isopropanol, or an ether such as diethyl ether, dioxane, 17 diethylene glycol, dimethyl ether or ethylene glycol. 18 Essentially equimolar amounts of the reactant are employed 19 although this is not essential and a molar excess of either may be used if desired. Reaction temperatures of from 21 M0-120°C, and preferably 70-100° C, are employed for best 22 results. When the reaction is essentially complete the (IV) employed directly without further purification in the ring-closure reaction leading to the quinolate (I). This is effected by heating at 200-300°C, and preferably at about 240-270°Co , for from about 10-30 minutes. Although not necessary s it is desirable to carry out the reaction in a high-boiling organic solvent such as dimethylsulfone , dodecylbenzene, biphenyl- diphenylether and similar solvents inert under the reaction conditions. At the end of the reaction period the mixture is cooled and the desired loweralkyl ¾-hydroxy-6 s, 7-disubstituted-quinoline-3-carboxylate recovered and purified by techniques known to those skilled in this art.

It has been found convenient to carry out the complete synthetic process without purification of the intermediate anil (IV), and in some cases without isolation of the 3-R^-¾-Rg-aniline (II). In preparing the loweralkyl 6-loweralkyl- -dlalk lamino-^-hydroxy-quinoline- 3-carboxylates of the Invention, the aniline II is convenient-ly obtained by catalytic reduction of the corresponding nitrobenzene in a lower alkanol, and in such cases we pre-fer to simply remove the catalyst and treat the alkanolic reaction mixture containing with the alkoxymethylene malonate.

The compounds of Formula I above form quaternary salts on heating with loweralkyl halides9 and such salts are contemplated by this invention. These salts are obtained by employing a molar excess of alkyl halide, and are readily purified by crystallization from solvents such salt as acetonitrile. The quaternary/of methyl 6-n-propy 1-7-dieth lamino-U-hydpoxy-quinoline-S-carboxylate and methyl 1 methyl-quinolyl ammonium iodide may be pictured structural- 2 ly as OH 3 Representative examples of other quaternary salts 4 are 3-carboethoxy~¾-hydroxy-6-n=propyl-7-diethylmethyl quinolyl ammonium bromide and 3-carbomethoxy-U-hydroxy-6- n-propyl-7-triethyl quinolyl ammonium iodide. These salts 7 are, like the parent compounds s highly active anticoccidial 8 agents. 9 The novel quinoline-3-carboxylates of Formula (I) 0 above may also be prepared by esterifying the corresponding 1 quinoline-3-carboxylic acid. This process is effected by 2 treating the free acid with a loweralkanol in the presence 3 of a mineral acid such as hydrochloric acid, sulphuric acid, * and the like. The esterification temperature should be 5 maintained at about 75~150°C., conveniently at about 100°C. 6 for several hours. The acid and excess alkanol may then be 7 removed in vacuo and the residual ester (I) isolated and 8 purified by conventional techniques such as neutralization, 9 extraction into and crystallization from organic solvents. 0 The compounds of Formula (I) are also preparable 1 from the corresponding quinoline-3-carboxylic acid halide 2 by reaction of an acid halide such as the acid chloride, 3 with a loweralkanol , e.g. methanol or ethanol, at about Ί 40-l60°Co The loweralkyl quinolate is isolated and puri-5 fied by standard techniques. 1 The 4-hydr-oxy-6-Rg-7-Ry-quinoline-3-carboxylic 2 acids, where R^ and R^ are as previously defined, referred 3 to hereinabove may be obtained by heating a loweralkyl Ί ester thereof with a base, such as an aqueous alkali metal hydroxide . The corresponding acid halides , such as 6 h droxy-6-Rg-7-Ry-qulnoline-3~carbon l chloride or bromide, 7 are synthesized by reacting the free acid with thionyl 8 chloride or bromide at an elevated temperature of about 9 60-90°Co 0 Coccidiosis is a widespread poultry disease 1 involving the invasion of caecal and intestinal mucosa by 2 coccidia, specifically protozoan parasites of the genus 3 Eimeriao The most important of these species are E. maxima, ¾ E. ascervulinas E. tenella, E,. necatrix , E. brunettl, Ei praecox and E. mitis. Related species of coccidla such 6 as E. meleagridis and E. adenoides cause coccidiosis in 7 turkeys. When left untreated, the severe forms of the 8 disease leads to poor weight gain, reduced feed efficiency, 9 reduced egg production and high mortality. For these 0 reasons s the effective control of coccidiosis is highly 1 important to the poultry industry. 2 It has been discovered that the loweralkyl 6-Rg-3 7™Ry-i*"hydroxy-quinoline-3-carboxylates of Formula I above, 4 and the quaternary salts thereof, are highly effective for 5 the treatment and prevention of coccidiosis, 6 In using the compounds of this invention in the 7 treatment and prevention of coccidiosis, they are con-8 venientl fed to poultry as a component of the feed of the 9 animals although they may also be given dissolved or sus-0 pended in the drinking water. According to one aspect of f 1 compounds of Formula I above are present as an active anti- 2 coccidlal ingredients Such compositions comprise the 3 quinolates intimately dispersed oradmixed with an inert ¾ carrier or diluent <» By an inert carrier is meant one that is nonreactive with respect to the quinolate and that may 6 be administered with safety to the animals. The carrier or 7 diluent is preferably one that is or may be an ingredient 8 of the animal feed and is usually itself an element of 9 poultry sustenance, 0· The compositions which are a preferred feature 1 of this aspect of the Invention are the so-called feed 2 supplements in which the active ingredient is present in 3 relatively large amounts and which are suitable for *1 addition to the poultry feed either directly or after an intermediate dilution or blending step,, Examples of 6 carriers or diluents suitable for such compositions are 7 solid, orally ingestables nutritive carriers such as 8 distillers' dried grains s corn meal, citrus meal, fermenta-9 tion residues, ground oyster shells, wheat shorts, molasses 0 solubles, corn cob meal, edible vegetable substances, 1 toasted dehulled soya flour, soybean mill feed, antibiotic 2 mycella, soya grits, crushed limestone and the like. The 3 quinolate is intimately dispersed or admixed throughout the 4 solid inert carrier by methods such as grinding, stirring, 5 milling or tumbling- By selecting proper diluents and by 6 altering the ratio of carrier to active ingredient, com-7 positions of any desired concentration may be prepared. 8 Formulations containing from about 1% to about *»0¾ by 9 weight, and preferably from about 2-25% by weight of active 0 ingredient are particularly suitable for addition to by weight of quinolate are very satisfactory. The active compound is normally dispersed or mixed uniformly in the diluent but in some instances may be sorbed on the carrier. The optimal cpncent ation of coccidiostat in these feed supplements will depend to some extent on the particular compound employed,, Since it is convenient for the feed manufacturer to use about one pound of feed supplement for each ton of finished feed, the preferred concentration of any one of our coccidiostats in a feed supplement is partly a function of the level of active ingredient desired in the finished feed.

Examples of typical feed supplements containing a compound of this Invention dispersed in a solid carrier are : lbs. A. Methyl 6-n-propyl-7~diethylamino-i»-hydroxy quinolate-3-carboxylate . „ » 5.0 Wi©sit shorts 9 *0 Methyl 6-n-propyl-7-diethylamino=¾-hydroxy quinoline-3-carboxylate . . „ . . 5·0 Amprolium · · » . . . . · 20.0 Wheat standard middlings. . . . 75.0 These and similar feed supplements are prepared by uniformly mixing the quinolate with the carrier or carriers. · The feed supplements of the type illustrated here- inab'ove are usually further diluted with materials such as corn meal or soybean meal before being incorporated in the animal feed. In this intermediate processing step the level of coccidiostat in the carrier is brought down to from about 0.1$ to about 1„0¾ by weight. This dilution serves to facilitate uniform distribution of the substance - tains a source of fat, protein, carbohydrate, minerals, vitamins and other nutritional factors.

The amount of loweralkyl 6-Rg-7-Ry-1<-hydroxy-quinoline-3-carboxylate (where Rg and R„ are as previously defined) required for effective control of coccidiosis will depend upon factors such as the specific compound employed, the type and severity of infection, and duration of treat- . mento In any event, only a minor amount is necessary in relation to the total feed or drinking water consumption. Good prophylactic results are achieved when the feed administered to poultry contains from about 0.0005$ to about 0.05$ by weight of our quinolate compounds, and preferably from about 0.00075$ to about 0.0125$ by weight. With the preferred compounds of the invention excellent results are achieved at dose levels in the lower end of this range. For therapeutic use, higher levels of up to 0.1$ by weight of feed may be used effectively for short periods of time.

Administration via the drinking water of the birds is often employed in the therapeutic use of our com-pounds since poultry with coccidiosis are apt to consume less solid feed than normal birds. The compounds may be added directly to the drinking water. Alternatively, water-soluble powders may be prepared, in which the coccidiostat is intimately admixed with. a suitable carrier, such as dextrose or sucrose, and these powders added to the drinking water of poultry as necessary. Such water-soluble powders may contain any desired concentration of coccidio- stat, and preparations containing from 1-25$ by weight of active compound are suitable. y Our loweralk l 6-Rf-=7-R7-i*-hydroxy-quinoline-3 carboxylates are active against the important species of coccidia. T^eir potency against E. tenella and E. brunetti is of particular significance inasmuch as these lead to serious forms of Infection.

According to an additional aspect of our inven-tions there are provided anticoccidial compositions contain-ing a quinolate of Formula I above together with a second coccidiostat such as amproliums zoalene, nicarbazin and the like. There is evidence that compositions containing both a quinolate and amprolium afford better control of coccidiosis than is obtainable with either substance alone.

Thus, poultry feed compositions containing from about 0.001-0 o 005¾ by weight of methyl (or ethyl) -6-n-p opy 1-7-diethyl-amino-4-hydroxy-quinollne- 3-car ox late and from about 0.005-0 o 015¾ by weight of amprolium afford excellent con-trol of coccidiosis in poultry. Our feed compositions may also contain other substances useful for poultry well-being such as vitamins s antibiotics or growth promotants.

The anticoccidial activity of the loweralkyl 6-Rg-7-Ry-i<-hydroxy=-quinoline-3«=carboxylates is determined by feeding groups of straight run White Leghorn chicks a ration containing graded concentrations of quinolate com-pound and orally inoculating the birds with sporulated oocysts of the coccidla on the second day of the test. With E. tenella 50 , 000 oocysts are used, and with E. brunetti a E. maxima and E. acervullna 100 , 000 oocysts are employed.

The birds are fed the medicated diet for a period of days ( 5-f8) s then weighed and sacrificed, and examined for remain- o t d or lesions due to co idio t i s y 1 these assays appear In U.S. Patents Nos . 3,020,200 for 2 E. tenella and 3,211,610 for E. brunettl and other species . ) 3 The activity of the quinolate is expressed in terms of the k weight percent concentration in the feed that provides the desired control of the Infection. As previously stated, 6 our compounds have significant activity at feed concentra- 7 tion levels of about 0.0005 to about 0.05% by weight, the 8 precise optimum level depending on severity and type of 9 infection. 0 The anticoccidial activity of representative com- 1 pounds of this invention against E. tenella and E. brunettl 2 is as follows: 3 Dose Level 4 Compound {% by weight in feed) OH E. brunettl E. tenella 6 CH, n-C^H^ N(¾H5)2 0.0015 0.003 7 C2H5 (C2H5)2 0.0015 0.003 8 CH3 n-cHH9 N(C2H5)2 0.0015 0.003 19 CH3 i-C3H7 (C2H5)2 0.003 0.006 0 C2H5 N(C2H5)2 0.003 0.0125 U.S. 21 The assay procedure is found in Example 8 of/Patent U.S. 22 3,020,200 and Example 2 of /Patent 3,211,610. 2 211 610. Meth l 6~n- ro l-7-dieth lamino-M-h drox - Millions of Concentra- No. % % Weight Oocysts In tlon in Feed Chicks Mortality Gain Surviving Birds E. tenella 0.00075 20 10 79 8.2 0.0015 20 0 105 6.0 0.003 20 0 96 3.2 0.006 20 0 107 0.1 Infected Control 120 57 8 20.0 Normal Control 40 0 100 0.1 E . maxima 0.00075 20 0 78 0.0015 20 0 85 0.003 20 0 93 0.006 20 0 105 Infected Control 120 0 73 Normal Control 10 0 94 E. brunettl 0.0001» io 10 83 0.00075 10 0 88 0.0015 10 0 104 0,003 10 0 107 Infected Control 60 8 43 Normal Control 20 0 109 The following examples are given for the purpose EXAMPLE 1 Methyl 6-n-Propyl-7-Diethylamino-4-Hydroxy-Quinoline~3--Carboxylate 52.3 G. of 2-n-propy1-5-nitro-N sN-dieth 1 aniline in 500 ml. of methanol is hydrogenated in the presence of 3.5 o of 5% palladium on carbon catalyst at room tempera-ture and under a positive hydrogen pressure of about 40 poS oi o When the theoretical amount of hydrogen is absorbed, the hydrogenation is stopped and the catalyst removed by filtration. The filtrate is concentrated under reduced pressure to an oil consisting predominantly of 2-n-propyl-5-amino-N,N~dlethyl aniline , which product is used directly in the next step without further purification.

To 48» 7 g. of the oil obtained as described immediately above there is added 43. g. of dimethyl methoxymethylene malonate in 1 liter of toluene. The re-suiting mixture is refluxed for 2 hours and then concen-trated under reduced pressure to remove the toluene to afford a residue of 86 g. of the anil methyl a-carbomethoxy-β-( 3-diethylamino-4-n~propyl-anilino)-acrylate « This it substance is used as /is without further purification. 1500 Ml. of dodecyl benzene is heated to 250-2bO°C, with stirring and 86 g„ of the anil is added over a period of about 5 minutes The resulting solution is stirred at 250-260°C. for 15=20 minutes and then allowed to cool, with stirrings, to room temperature. The resulting solid is collected by filtration, washed with acetone at room temperature and dried to afford substantially pure methyl 0=n~propyl=7»dlethylamino-4-hydroxy-qulnoline-3- carboxylate, n p. 198-204°C. This product is dissolved in 1 carbon, filtered and the filtrate chilled to 0-5°C. The 2 product crystallizes and is recovered b filtration, m.p. 3 212°C. 4 A second crop is obtained by reheating the dodecyl benzene filtrate at 250-260°C. for 15 minutes, cooling it (5 to room temperature, and adding 400 ml. of acetone. The 7 resulting solid methyl 6-n-propyl-7-diethylamino-4-hydroxy- 8 quinoline-3-carboxylate is recovered and purified in the 9 same manner as stated above. 0 EXAMPLE 2 1 Ethyl 6-n-Propyl-7=Diethylamino-4-Hydroxy-Quinoline-3-2 Carboxylate 3 7.8 G. of diethyl ethoxymethylene malonate in 4 200 ml. of toluene Is added to 7.5 g. of 4-n-propyl-3-5 diethylamino aniline (alternatively defined as 2-n-propyl-ό 5-amino»N,N-diethyl aniline). The resulting mixture is 7 refluxed for 2 hours and then concentrated to dryness in 8 vacuo to remove the solvent and the alcohol formed as a 9 reaction product. The resulting residue consisting of 0 ethyl a~carboethoxy-p-( 3-dlethylamino-4-n-propyl-anillno)-1 aerylate is added to 400 ml. of rapidly stirred dodecyl 2 benzene at 250-260° C. The mixture is held at this tempera-3 ture for 15 minutes and then allowed to cool to room tem-4 perature. The resulting solid is removed by filtration and 5 washed with acetone to give 5 g. of ethyl 6-n-prop l-7-6 diethylamlno-4-hydroxy-quinoline-3-carboxylate, m.p. 204-7 206°C. 8 When the above process is repeated using -n-9 propy1-3-dimethylamino aniline as starting material there 1 EXAMPLE 3 2 Methyl 6-Isobutyl-7-Dlethylaralno-¾-Hydroxy-Qulnoline-3- 3 Carboxylate ^ 10 Go of 2-isobutyl-5-nitro-N,N-diethyl aniline in 100 ml. of methanol are hydrogenated at, room temperature b over 0.7 g. of palladium-carbon catalyst under a positive 7 hydrogen pressure of about *40 p.s.i. until the theoretical 8 amount of hydrogen is absorbed. The catalyst is then 9 removed by filtration and the mixture concentrated in vacuo to an oil of 4-isobutyl-3-diethylamino aniline. To this 11 oil there is added 8 g. of dimethyl methoxymethylene 12 malonate in 200 ml. of toluene. The resulting mixture is 13 refluxed for 90 minutes and then concentrated to dryness ^ ϋ vacuo to afford a residue of methyl a-carbomethoxy-β- 15 ( S-diethylamlno-^-isobutyl-anilinoJ-acrylate . 16 This latter substance is added directly to 300 ml. 17 of dodecyl benzene at 250-260° C. The mixture is stirred at 18 that temperature for 20 minutes. It is then cooled to room 19 temperature and the resultin solid removed by filtration, washed with acetone and dried to afford methyl 6-isobutyl- 21 7-diethylamino-1i-hydroxy-quinoline-3-carboxylates m.p. 206- 23 EXAMPLE 4 2¾ Methyl b-sec-Butyl-7~Diethylamino-lJ-Hydroxy-Quinoline-3- 25 Carboxylate 26 When the process of Example 3 is repeated employ- 27 ing as starting material 2-sec-butyl-5-nitro-N,N-diethyl 28 aniline, there is obtained methyl 6-sec-butyl-7-diethyl- 29 amino-^-hydroxy-quinoline-S-carbox late , m.p. 239-2¾3°C.

EXAMPLE 5 A. Methyl 6-n-Butyl-7-Diethylamino-4-Hydroxy-Quinoline-3- Carbox late 32 G. of 2-n-butyl-5-nitro-N,N-diethyl aniline in 300 ml. of methanol are hydrogenated at ropm temperature using 2 g. of 5% palladium-on-carbon catalyst and under about 40 p.s.i. of hydrogen pressure. The hydrogenation is allowed to proceed until the theoretical amount of hydrogen is absorbed, and at the end of this time the catalyst is filtered off. The filtrate is concentrated to dryness to afford 30 g. of an oil consisting predominantly of 2-n-butyl-5-amino-N,N-diethyl aniline. This material is divided into two equal portions, one being used in the re-raainder of this experiment and the other in the experiment described in part B following.

To 15 g. of the foregoing product there is added 15 g. of dimethyl methoxymethylene malonate in 300 ml. of toluene. This mixture is refluxed for 2-1/2 hours and the toluene then removed by concentration in, vacuo. The residual anil is not purified further but is added directly to 500 ml. of dodecyl benzene at 250-260°C. The mixture is stirred at this temperature for 30 minutes and then cooled slowly to room temperature. The solid product is separated by filtration, washed with acetone and dried to afford 5.6 g. of methyl 6-n-butyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate, m.p. 200-205°C. ; B. Ethyl 6-n-Butyl-7-Dieth lamino-4-Hydroxy-Qulnoline-3- Carbox late G. of the aniline derivative obtained above is reacted with diethyl ethox methylene malonate and the re- 1 EXAMPLE 6 2 Methyl 6-Isopropy1-7-Dlethylamino-M-Hydroxy-Quinoline-3- 3 Carboxylate M 26 G. of 2-iso ropyl-5-nitro-N,N-diethyl aniline are hydrogenated to 2-isopropyl-5-amino-N,N-diethyl aniline, 6 this latter material reacted with 22 g. of dimethyl 7 methoxymethylene raalonate in 500 ml. of toluene, and the 8 resulting anil heated in 700 ml. of dodecyl benzene, 9 following the procedure of Example 1, to afford 12.3 g. of 0 methyl 6-isopropy1-7-diethylamino-^-hydroxy-quinoline-S-1 carboxylate, m.p. 2M6-253°C. 2 When this procedure is repeated employing 2-3 isopropyl-5-nitro-N,N-dimethyl aniline and diethyl ethoxy-¾ methylene malonate, there is obtained ethyl 6-isopropy1-7-5 dimethylamino-^-hydroxy-quinoline-S-carboxylate . 6 EXAMPLE 7 7 A. Methyl 6-Ethy1-7-Diethylamino-¾-Hydroxy-Quinoline-3-8 Carboxylate 9 'ΊΊ.Ί G. of 2-ethyl-5-nitro-N,N-diethyl aniline in 0 400 ml. of methanol is hydrogenated at room temperature 1 using 2 teaspoons of Raney nickel catalyst under about 40 2 p.s.i. of hydrogen pressure. When hydrogen uptake is 3 complete, the catalyst is filtered off and the solution 4 divided into two equal portions. To one portion there is 5 added 17. ¾ g. of dimethyl methoxymethylene malonate, and 6 the mixture heated for one hour on a steam bath. The re-7 action mixture is then evaporated to an oil in vacuo, which 8 oil consists predominantly of the anil methyl a-carbo-9 raethoxy-P-(3-diethylamino-¾-ethyl-anilino)-acrylate. This 0 material is added directly to 500 ml. of dodecyl benzene 1 suiting solid is collected by filtration and recrystallized 2 from dimethy lformamide to afford substantially pure methyl 3 6-ethy 1-7-dieth lamino-^-hydroxy-quinoline-3-carboxylate , *» m.p. 244°C.

B. Ethyl 6-Ethyl-7-Diethylamino-JJ-Hydroxy-Quinoline-3- 6 Carboxylate 7 To the other half of the methanolic solution 8 obtained above there is added 21.6 g. of diethyl ethoxy- 9 methylene malonate . This reaction mixture is treated as described above to afford ethyl 6-ethyl-7-diethylamino-¾- 11 hydroxy-quinoline-3-carboxylate s m.p. 251°C. 12 ' EXAMPLE 8 13 3-Carbomethoxy-¾-Hydroxy~6-n-Propyl-7-Qulnolyl Dlethylmethyl I1* Ammonium Iodide To 2.5 g. of methyl ό-η-propy 1-7-diethylamino-1*- 16 hydroxy-quinoline-3-carboxylate is added 15 ml. of methanol 17 and 25 ml. of methyl iodide. The resulting solution is 18 heated under reflux for 5 days. The solvents are then re- 19 moved in vacuo and the residue crystallized from aceto- 20 nitrile to give 1.05 g. of 3-carbomethoxy-^-hydroxy-6-n- 21 propyl-7~quinol l dlethylmethyl ammonium iodide. Re- 22 crystallization from acetonitrile affords substantially 23 pure material, m.p. 126-127°C. 2k . EXAMPLE 9 Methyl 6-n-Propy l-7-Diethylamino-1i-Hydroxy-Quinoline-3- 26 Carbox late 27 To a suspension of 0.6 g. of 0-n-propyl-7-diethyl- 28 amino- ¾-hydroxy=quinoline-3-carboxylie acid in 20 ml. of 29 methanol there is added 1.5 ml. of concentrated sulfuric hours and most of the alcohol then removed by concentra-tlon in vacuo. The residue is cooled, neutralized with 10% sodium carbonate and the resulting precipitate separated and crystallized from dimeth Iformamide to give substan-tially pure methyl 6-n-propy1-7-diethylami'no-4-hydroxy-quinoline-3-carboxylate . 1 Go of 6-n-prop 1-7-diethylamino-4-hydroxy-quinoline-3-carboxylic acid is refluxed in benzene for 7 hours with a molar equivalent of thionyl chloride. The resulting acid chloride. is separated and refluxed for 5 hours in 40 ml0 of methanol. The reaction mixture is then filteredj, the filtrated chilled and the solid product separated. It is recrystallized from dimethylformamide to give methyl 6-n-propy1-7-diethylamino-4-hydroxy-quinoline-3-carboxylate «, The starting materials for preparing the lower-alk 1 6-loweralky1-7-dialkylamino-4-hydroxy-quinoline-3-carboxylates of this invention are 3-dialk lamino-4-loweralkyl anilines (alternatively named as 2-loweralkyl-5-amino-NsN-dialkylanilines) of the formula where is loweralkyl and Y2 is diloweralkylamino. Such materials are obtained on catalytic hydrogenation of the corresponding nitro compounds using a palladium or Raney nickel catalyst. Those nitro compounds which are not specifically described in the literature may be prepared by the procedures stated below for making the starting com ounds of Exam les 1-7 above. 1 A. solution of 4 ml. (77 g.) of nitric acid 2 (d 1.42) in ,75 ml. (138 g.) of sulfuric acid (d 1.84) is 3 added dropwise with vigorous stirring to 100 g. of n-propyl- benzene over a period of about 2 hours. During the addition, the temperature is kept at 25-30°C. with external 6 cooling. After the addition is complete, the mixture is 7 stirred for an additional 2 hours at 25-30°C. and then for crushed 8 l hour at 40°C. The mixture is then poured onto -chopped 9 ice with stirring and extracted with 3 x 75 ml. of hexane.

The hexane extracts are combined, washed successively with 11 50 ml. portions of water, aqueous sodium bicarbonate, and 12 finally with water again. The hexane solution is dried 13 over magnesium sulfate, filtered and the hexane removed l1* under reduced pressure. The residual oil is distilled under reduced pressure using a spinning band fractionating 16 column,. The desired o-isomer is the lowest boiling isomer. 17 It boils at 118°C./15 mm., and this fraction of the dis- 18 tillate is collected to give 2-nitro-n-propylbenzene . 19 Other 2-nltro-alkylbenzenes are prepared in the same manner by nitration of the appropriate alkyl benzene. 21 Representative examples have the following constants: 22 2~nitro-Isobut lbenzene , b,p. 124°C./1 mm.; 2-nitro-s- 23 butylbenzene, b.p. 122°C./13 mm. ; 2-nitro-n-butylbenzene , 24 b.p. 132°C/1 mm.; 2-nItro-isopropylbenzene , b.p. 115°C./ 15 mm. 26 B. 2-n-Propyl- ,N-Diethylaniline : 79 G. of 2-nitro- 27 n-propylbenzene in 600 ml. of absolute ethanol and 64 ml. 28 of acetaldehyde is hydrogenated in the presence of 5 g. of 29 5% palladium-on-carbon catalyst at room temperature and under about 40 p0s9io hydrogen pressure. After the hydro- absorbed due to the excess acetaldehyde present) the catalyst is removed by filtration and the alcohol removed under reduced pressure. The residue is distilled under reduced pressure to afford 2-n-propy1~N >N-diethylaniline , b.p. 127-133°C/28 mm, Other 2-alkyl- „N-diethylanilines are prepared in the same way and have the indicated properties: 2-isobutyl-Ν,Ν-diethylaniline, b.p. 124=l27°C./25 mm.; 2-sec-butyl-N,N-diethylanillnes b.p. 129°C./25 mm. ; 2-n-butyl-N,N-diethylaniline, b.p. l43°C./29 mm.; 2-isopropyl-N,tidiethylaniline, b.p. 126°C./28 mm. Use of formaldehyde or proplonaldehyde in place of acetaldehyde affords the corres-ponding Ν,Ν-dimethy1 or Ν,Ν-dipropyl aniline.

A different procedure is the following, as applied to making 2-ethyl-N,N-diethylaniline : A mixture of 100 g, of 2-ethylaniline and 150 g. of trlethylphosphate is stirred and heated to about 160°C. When the exothermic reaction subsides , the mixture is stirred and heated at 200°C. for 4 hours. The mixture is cooled and to it is carefully added a solution of 100 g. of sodium hydroxide in 500 ml. of water. The mixture is stirred at room temperature for 12 hours . The precipitated with oil is extracted 4«t© ether. The ether extracts are then dried, evaporated to dryness and the residue distilled at atmospheric pressure. The fraction distilling at 220°C. is 2-ethyl-NsN-diethylaniline.

C. 74 Go of 2-n~propyl-N,N-diethylaniline is added, with stirring and cooling, to 400 ml. of sulfuric acid (d 1.84). The temperature during the above addition is held below 20°C. The solution is then cooled to 0°C. and 1 sulfuric acid (d 1.84) is added dropwise, keeping the between and 2 temperature a 0° ¼ Other 2-alkyl-5-nltro-N ,Ν-diloweralk lanilines 6 are prepared in the same way from the appropriate starting 7 material, representative examples being: 2-isobut l-5-8 nitro-N,N-diethylaniline, b.p. ^-^^./0.75-1.0 mm.; 9 2-sec-butyl~5-nitro-NsN-diethylaniline, b.p. 135°C./1,3 mm. j 0 2-n-butyl-5-nitro~N,N-diethylaniline, b.p. 1¾3°C./1.65 mm. ; 1 2-isopropyl-5-=nitro-NsN~dlethylanilines b.p. 12¾°C./1. ¾ mm. ; 2 and 2-ethyl-5-nitro-N8N-diethylanilines b.p. 126°G./0.5 mm.

Claims (1)

1. 11 HAVING HOW particularly described and ascertained the nature of our said invention and in what manner the same is to^be performed, we declare that what we claim is 1. The process for preparing a compound of the formula wherein is loweralkyl, R^ is loweralkyl of 2- carbon atoms, and R^ is diloweralk lamino that comprises heating an aer late of the formula H wherein R^, Rg and R^ are as previously defined. 2o The process of Claim 1 wherein R^ is methyl or ethyl, R^ is n-propyl and R^ is diethylamino. 3o The process for preparing the loweralkyl 6-Rg-7-R7-1*--hydroxy-quinoline-3°carboxylate of Claim 1 that comprises treating a compound of the formula with a compound of the formula R OCHC(COOR3)2 to obtain an aerylate of the formula 11191 and heating said aer late 9 where R^, Rg and R^ are defined in Claim 1. ¾. The process for preparing the loweralkyl 6-Rg-7-Rj-^-hydroxy-qulnoline-3-carbox late of Claim 1 that comprises treating a compound of the formula OH with a compound of the formula R3-OH where R^ is hydroxy or halo, and previously defined. A compound having the structural formula OH > where R^ represents loweralkyl; Rg represents lower alkyl of 2-Ji carbon atoms, and R^ represents diloweralkylamino. and. quaternary salts thereof. 6o A compound of Claim 5 wherein R^ represents methyl o ethyl. 7i The compound of Claim 5 which is methyl 6-n-propyl-T-diethylamino-^-hydroxy-quinoline-S-carboxylate . 8. The compound of Claim 5 which is ethyl 6-n-propyl-T-diethylamino-^-hydroxy-quinoline-S-carboxylate . 9. The compound of Claim 5 which is methyl 6-n-butyl-T-diethylamino-^-hydroxy-quinoline-S-carboxylate. 10. The quaternary salt of a compound having the formula OH t where R^ represents loweralkyl; Rg represents loweralkyl of 2- carbon atoms, and R7 represents diloweralkylamino, 11. An anticoccidial composition comprising a quinolate of the formula OH where R^ represents loweralkyl; R^ represents loweralkyl of 2-4 carbon atoms , and R^ represents diloweralkylamino intimately dispersed in an inert edible carrier. 12 o The composition of Claim 11 wherein the carrier is a solid poultry feed additive and contains 1119 13. The composition of Claim 11 wherein the quinolate is methyi-o-n-propyl^-dieth laruino-^-hydroxy-qulnoline-S-earboxylate . 1Ί. A composition useful in the control of coccidiosis that comprises a poultry feed containing a minor but anticoccidially effective amount of a quinolate having the formula OH where R^ represents loweralkylj Rg represents loweralkyl of 2- carbon atoms, and R^ represents diloweralk lamino. 15 o The composition of Claim 14 wherein the poultry feed contains from about 0.0005$ to about 0.05$ by weight of quinolate. 16 The composition of Claim 14 wherein the poultry feed contains from about 0.00075$ to about 0.0125$ by weight of quinolate. 17. The composition of Claim 16 wherein the quinolate is methyl-6-=n-propyl-7~diethylamino-^-hydroxy quinoline-3-carboxylate .