DE1695406A1 - Quinoline carboxylic acid esters and processes for their preparation - Google Patents

Description

P 16 95 406 6-44 New documents

MERCK ft CO., INCORPORATED 126 East Lincoln Avenue * Rahway, N.J. 07065, V.St.A.

Quinonecarboxylic acid ester and method of preparation

the same

The invention relates to quinoline carboxylic acid esters and processes for making the same. The new connections are for Useful in combating coccidiosis. As such coooidiostats they are very effective «

An object of the invention is to create a new class of ™ Quinoline carboxylates and providing another goal a group of low mol-6,7-disubstituted-4-hydroxy-quinoline - ^ - oarboxylatea, which more powerful antlooooldose feed than the so far described represent. In particular, the compounds according to the invention are low-molecular-alkyl-6,7-disubstituted-4-hydroxyohinoline-3-carboxylates, in which the 6-substituent is low-molecular-weight alkyl having 2 to 4 carbon atoms and the 7-3 substituent is a di -niederao-lv-allcylaainorest 1st · Sin continue ·· Ζ1 · 1 is the statement · of an oheeisohen synthesis of these Subatanaes

_m ι. 109815/2191 '

11 191

by means of a heat-induced cyclization of the anil, which is described in the conversion of a 3,4-diol Obtains aniline with di-lower molar alkyl alkoxymethylene malonate. The invention further relates to anticoecldial wetnesses such substituted quinolines as the active ingredient either alone or together with one or more others Coccidiostatilca contain »as well as the method of treatment of coccidiosis with such hates

The invention relates to compounds of the general '

formula

, -COOR,

in which Rz is lower molar alkyl, Rg is lower _{molar alkyl having 2 to 4 carbon atoms and R 7 is} di-lower molar alkylamino »a process for the preparation of these compounds» which is characterized in that one is a compound of the general

formula

* COOR,

^r 6t V cm

I Ii * *

wherein Ry R ₆ and R ₇ which whether "n have the meaning given," rhitsti or that the corresponding ChinolincarbonsMure or their SMureohlorid in aa check catfish known in the nan-nlederBol. Alkyleater transferred eowle compounds of Foreel

109815/2191

■ - 2 -

in which R ₅ , R ₆ and R _{7 have} the meanings given above.

Examples are R, methyl »ethyl, propyl or butyl; Rg ethyl, n-propyl, isopropyl or η-butyl and R ~ dirne thylamino, Diethylamino or di-η-propylamine

The quaternary salts are also within the scope of the invention is obtained in the reaction of the quinoline I with a low molecular weight alkyl halide.

In the case of the preferred compounds according to the invention, H, methyl or ethyl and the substitution at the 6- and 7-positions is 6-p = propyl-7-ethylamino and 6-n-butyl-7-ethylamino. This group of substances is ea » Which has the highest degree and the broadest spectrum of anticoccidial activity, even if all the substances represented by formula I are good coeidiostats α

Examples of specific quinoline compounds within the scope of the invention are methyl 6-n-propyl-7-diethylamino-4-hyaroxy-quinoline-3-carboxylate, ethyl 6-n-propyl 1-7-diethylamino -4-hydroxy-quinoline -3 "carboxylate methyl-6-n-buty 1-7-dläthylemino-4" -hydroxyquinoline-3 ^ carboxylate _t methyl-6-n-propyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate and Methyl 6-n-propyl-7 "di ~ n-propylamino» 4-hydroxyohinoline-3-carboxylate _{or the like} .

, 109815/2191

The quinolates according to the invention are made from one lin With the structure formula

-IU-AnI-

II

synthesized by reacting the aniline with a di-lower oil alkyl lower molar, alkoxy net hy lenmalonate of the structure

R ₃ OCHC (COOR ₃ ) ₂

III

The immediate reaction product is the anil with the structure

• COOR,

IV

In the compounds II, III and IV the symbols R-, R ₆ and R ₇ correspond to the definition given above for formula I. ß- (, ^ - I ^^ - Rg-anilino) -aorylate define. The setter (IV) is then converted to kiedermoio-alkyl-4-hydroxy-6-R ₆ -7-R ₇ -ohinolin-3-carboxylate by request at elevated temperatures

109815/2191

The reaction of the aniline (II) with the maloate ester (III) is preferably carried out in an inert medium, such as a low molecular weight alkanol, e.g. B. methanol, ethanol or Iaopropanol or an ether such as diethyl ether, dioxane, diethylene glycol or ethylene glycol. One applies substantially equimolar amounts of Heaktionsteilnehmer on if this lot also not decisive _c and, if desired, a molar Upper shot of a can be used it, "In order to achieve the best results Reaktionsteaperaturen from 40 to 120 ⁰ C and preferably 70 to 100 ⁰ C used. When the reaction is essentially complete, the solvent can be removed by known methods and the anil (IV) can be used directly, without further purification, in the ring closure reaction which leads to the CM inolate (I). This is achieved by heating at 200 bie 300 ⁰ C and preferably at about 240 to 270 ⁰ G for about 10 to 30 minutes. Although not necessary, it is desirable to convert it into a high-boiling organic substance, such as dintthylsulfone, dodecylbeniol, bi-phenyl, and the like, under the reaction conditions in-

#ttt n Maungeaittel to carry out. Α «the end of the response time

_h IU OeeiMh cools down and that he «Un | Oh1e Iied _e raol.-alkyl-4-hy-

obtained and purified by means of well-known processes.

109815/2191

BATH ORIGINAL

6 16SS4Ö6

It has proved to be zweokmässig, the entire Syηtheseverfahr en without purification of Anil-Zwieche "products (tV) and run 3-R in some cases, without isolation of ₇ ~ 4-R ₆ -Anilina (II)" In the preparation of the inventive Jiiedermdl.-Alkyle-niedermol.-alkyl-T-dialkylamino ^ -hydroxy-quinoline-J-carboxyla- ^ te one obtains the aniline II in an elongated manner by catalytic reduction of the corresponding nitrohenzene in a low molecular weight alkanol and in such cases it is preferred »Simply separate the catalyst and treat the alcoholic reaction mixture» which contains the 3 ~ R7 = 4-R ₆ -aniiine with the alkoxymethylene malonate «

The compounds of the above formula I form when heated with never » dermolekulareη alkyl halides quaternary salts and such salts Ze are within the scope of the invention »/ These salts are obtained by the Use a molar excess of the alkyl halide and they can be easily »never Acetonitrile »clean» the quafcernary salt of methyl-6-n-propyl * · T-diethylamino ^ -hydroxy-quinoline-J-earboxylate and methyl iodide, which 3-Carl) omethoxy-4-hydro3cy-6-i! i-propyl-7-diafchylmethylohinolyl-amraonlumjodId is called »can by the structural formula

109315/2191

COOCH

^H 5 ^C 2 Ah,

being represented.

Typical examples of other quaternary salts are 3-carbethoxy-4-hydroxy-6-n-propyl-7-ethylmethyl-quinolyl-ammonium bromide and S-CarbomethoxyH-hydroxy-e-n-propyl-T-triethyl-quinolyl-aBimoniumjodidc These salts are in the same way never the parent compounds highly active anticoccidial agents.

The new quinoline-3-carboxylates of the above formula (I) can also be prepared by esterifying the corresponding quinoline-3-carboxylic acid. This reaction is achieved by treating the free acid with a low molecular weight alkenol in the presence of a mineral acid such as hydrochloric acid, sulfuric acid and the like. The esterification temperature should be kept at about 75 to 150 ^° C., expediently at about 100 ^° C., for several hours. The acid and excess alcohol can then be removed in vacuo and the remaining ester (I) can be isolated and purified using conventional methods such as neutralization, extraction in organic solvents and crystallization from organic solvents »

109815/2191

The compounds of formula (I) are also prepared from the corresponding quinolin ~ 5 ~ carboxylic acid halide produced * by reaction of an acid halide _f as the Säureohlorids with a low molecular weight alkanol, e.g., Bo methanol or ethanol, at about 40 to 160 The niedermolo-Alkylchinolat is isolated, and purified by conventional methods.

The 4 = 'Hydroxy = 6- = Rg-7'-R ^ ~ quinoline-3 "carboxylic acids, in which R ₆ and R ^ correspond to the meaning given above, which are described above, can be obtained by heating a low molecular weight alkyl ether thereof with a base, such as an aqueous alkali metal hydroxide. The corresponding acid halides such as 4-hydroxy-6-Rg-7-R.7-ohinolln-J-carbonyl chloride or bromide are produced by reacting the free acid with thionyl chloride or brontide at an increased . Temperature i ^p on about 60 to 90 ⁰ C produced '

The Ccseeidioee is a widespread poultry _{disease p} -weleite _ & en Infestation of the appendix and intestine eh glue membranes by Cocc-idießp specifically protozoisehe ⁵ parasites of the genus Mmeria einsohlieeet The most important species are Ec ma xima _t E _g aacervu ljua _t Ee te ne 11 Ec neaatri ", E, ... 'brjanettl" Eo ₁ praeppg and L with la ο related species of coccidia _s such as E ^ c ^ rael ^ eagridi ^ and Eo adeno idee call "Cocqidioee at Trutbebn _β Im unbebandeitea -" ^ ieteiid the echwc-rc form of ßrferankrting at a low

1 O381 572 1 9 1 ^BAD ORIGINAL

decreased puttering effectiveness, decreased egg production and a high mortality ■ «Ana is this öriinden an effective control of the coceldioae is of considerable importance for the oil industry »

ßa would be found that the. ^ • quinolii3-3-öarboxylal; e of the above formula I and their quaternary .Salts in a high mass for the treatment and prevention of oil doses are effective

In applying the erfindungsgemäaaen compounds for the treatment and prevention of Öoccidiöee they are in Kweckmässigar Wei _ ''# p to the poultry, as a constituent part of the $ IERF utters. bef lit tart _p if you also drink it in dissolved or suspended form.

Administering water can _or should one aspect of the invention create new masses? in which-the connections of the. Obigan formula I as an active.anblcoocldheHer constituent present i Maas en contain the Ghinolatg intimately dlspsrglert.

/ m _; with an inert carrier odai ¹ 'feftHimniiigsmitttl ,. With an 'inert "Krüger lijt" in -aoLohör. Au-Te ^ a ^ haäi d «r In. Oe ^ 3« Γ da »(ihiöoLat niolif raaktionsbarenietp, i« \ d. Den_ fieren loit

mitt ?! i &% ißTmviavsitan \ a <i ^, »e ^ mitmi, inm ^ 'Mis, i'-4i -', - ■} - :: u Iu ¹ I ϊί -} - Ή 'ϋ'χίίΐ kmm Uj3- -3 Lsi! Ibtifin

1895408

tell, the poultry food »

Masses, which a preferred 'execution fona'dleeee- Flee' points dex *. Invention aarsteilen, bind- "the so-called futtersmaätae, in which the active 'constituent in relatively large quantities is changing, and we lohe see for the addition of' fluge! Futter either 'directly or near' one a'wieefae nge scarf == t & Um VBTuinmimgB ^ or srisehatufe, suitable * for example of "embossers or"""VeräUnun'gflinlttelö, which are suitable for ^; such cash registers are solid, orally ingestible, nutritious carriers, such as dried 3? berber ₉ MsiameUl, oltrusm @ hl _? Pörmentationsrüekatäsde »ground oyster shells» WelEenkieie, soluble Melaeaebe'a-feandteile, MjIs -cob meal, edible vegetable substances, roasted flour nthttlste «üojaboiinen» & ojabohn «nfutter (Fermal),

ri, SöjagchsOt, ground -Kalkstein "and der-Daa öhlmAat" * is stamped throughout the entire .iagrteη. g diöpergiart; αύζι * "« / «rmisuhl; ailfetsls' / learn how · Z @ rrelb @ n, -

y Mahla «f; d» r. iiOfflfiaelv.eraieehen-. lkw & h rJüa - Güögsraitfeal h & -sI & - YeeUnustig des uk ^ ivmi ilsatax · -) ^ aIl'könfj-ö «" Siaaaä «-i ^ gll ^ feoi g £? / üDs @! iten r * ifieren fee ^ gsä:. -311 Ir ws ^ dian ^^ uii ^ iti- ^ iji ^ e laniage »/ 'wslöfe ψ @ i'eiiwa;'-iH'Ux;,' i -imö-" itTfrauiuHfeeta-a ^: iu ;! at? / a 2 Ms i5 © 3 *? ^ # ''

- »I ^ -I 'uzhhiuI-jts j§ # i§a3§ as«, w ^ law :; ^ vs purple t * S Cfmfoi

1695A06

Quinolate contain »Bind very satisfactory ο The active compound is usually evenly dispersed or mixed in the diluent, but can be adsorbed on the carrier in certain cases.« The optimal concentration of the cooeidiostat in these feed additives depends to a certain extent on the particular compound used it is expedient for the feed manufacturer _f as per tonne of finished feed apply a pound of feed additive, the preferred concentration iet any of the described C © ceidiostatika in a feed additive in part a function of the content of active inventory parts is desired in the finished feed

Examples of typical feed additives which contain an inventive Compound dispersed in a solid carrier

yyyy quinoline - ^ - carboxylate 5 _f O

Wheat Bran 95 , Q

yyyy ohinolin> 3 carboxylate 5 _P o

Amprolium 20 _Γ Ο

Wheat feed product 75 _f O

These and similar Futtermisätze be gleichmässlgeB mix dee Ctiißolats with the carrier otter the carriers stuborei tet ο ^

BAt)

- 10981B / 2191

«Ϊ́ 1 ec

The feed additives of the type described above are commonly diluted further with materials such as corn meal or soybean meal, ο before they are incorporated into the feed for domestic fowls In this LAT Bchengeschalteten processing stage the proportion of Coccidioetatikums in the carrier to about 0.1 is to about 1 * _o 0 wt # reduced ο This dilution is used to facilitate an even distribution of the substance in the finished feed. The finished feed contains a source of fat, protein, carbohydrates, "minerals, vitamins and other nutritional factors"

The amount of Niedermol _o ~ alkyl-6-Rg ~ 7 ~ ~ R7-4 hydroxy quinoline ~ ~ 3 - carboxy lat (wherein Rg and R ^ the definition given earlier, respectively), which is required for effective control of coccidiosis, depends on factors such as the particular compound used, "the nature and severity of the infection and the duration of treatment." In any case, only a small amount is required in relation to the total feed or drinking water consumption ο Good prophylactic results are obtained if the feed administered to the poultry contains from about 0.0005 to about 0.05 wt% _{, and preferably from about 0.00075 to about 0.05 wt%, of} the quinolate compounds. The preferred compounds of the invention provide excellent results with dosage levels at the lower limit of this range. For therapeutic use, higher levels of up to 0.1% by weight of the feed can be used effectively for short periods of time.

The administration in aera way Via the! Crinkwaeser of the birds is often in the therapeutic "application of the remedies beMötsstj aa poultry suffering from Cöocidioae" which "tend" to eat less solid food than normal birds "" These connections are added directly to the drinking water »» One can produce water-soluble pulpers in another way, in which the OoocicHoatatikuni is intimately mixed with buckets of paasenaen irtger * such as lextross or raw sugar «and these powders are added to the drinking water of the" öef lUgela as needed ο such water-soluble * = High powders can have any desired concentration Äes' das tat ikujns and preparations containing 1 to 25 of the active compound * are suitable

are effective against the important . u «d B _a tennettl is insofsi '' van hesondersr Betleutuög than this erneten to uen forms of

elmm -mltezep eeele & tsipee & t άβ $ Mritnümg

alette Waaafin g®e®lmtimv mel @ lm- ®ln O »it

1 ii 8 1 Λ / 2 1 i% AD

and the like, Ee are Beweiae or that masses which both a öhinolat ala also amprolium enthaltöHj better ControlIe the Ooeeldioae permit when they r zen with each of the two Substa _"?! is to achieve alone. Therefore, poultry-to-anmene acid containing about 0.001 0.005 methyl (or ethyl) 6 ~ n ~ pfopyl ~ 7 ~ diethyl amine ~ 4 ~ itjoline-i-carboxylate and about 0.005-0.015% gives an excellent control of coconut diet In the case of Saffaft gel * Bi® fnatlea ^ mlttelzuaaingieiisetzuBgen a "öh e_adere substances useful for the sweetness of the SeflUgeis" such as, ÄHtii> JL.otifia or growth-promoting agents

The Antlooceiaielle Activity of the ^^

Ehinolin-J ^ earboxylate is determined ₉ by feeding on sriappen we readers m 3J90horßkü! £ sn {"atraight run Whiie Xegborn. chlefes *") © ine food 7e? £? lter, .which various types of oil contain ions of the oil-loess compound "And the fögsl with sporeabiX ^ esdeH 'Oo ^ ystea the Wen & m second fag of the attempt orally iseiiopft". Tea de "50,000 Oösyeten veririeiide-t." Öd in the case of

. ! SaxiiBa .usd £ * 'jaeervuXiiaa * © etsi; man 10 © -OOÖ-öesj? ®! «« @i « ₀ Bm V8 ßüla wird-wShiiena one $ 3 iispantw ir © f3 <5-e> fag« n da «« ixkesKeS liitlsl ^ srda-heoe üiJit vezabxoioht,, « ie .. gs ««> § # ii «» d ^ «öölaoätet« na aaf

«Alud to suffered ίδ / 2 *.? 1

1695A06

USA patents 3,020,200 for E. Jfcenella and 3,211,610 for E. brunett1 and other species. The activity of the quinolate is expressed as the concentration in weight _c 54 in the feed which gives the desired control of the disease? As noted above, the compounds of this invention sieigen a significant activity at concentration levels putter from about 0.0005 to about 0.05 6EW _c ^ _t with the precise optimum level depends on the severity and type of infection.

The anticoccidielle activity typical erfindungagemässer compounds against E "tenella and E. brunetti shows the following list%

Connection OH

Dosing uncertainty level (weight # in putter)

COOR,

E ₂ nC, H ₇ R ₇ Ε. brunette1 1 0-9-8 E. tenella 003 CH ₃ nC ₃ ~ H ₇ K (C ₂ H ₅ ) ₂ 0.0015 0, 003 C ₂ H ₅ HC ₄ H ₉ H (C ₂ H ₅ ) ₂ O _e O015 0, 003 CH ₃ 1-P ₃ H ₇ K (C ₂ H ₅ Y ₂ 0.0015 ° » 006 GE ₃ ⁿ ~ 4 9 H (C ₂ H ₅ ) ₂ 0.003 0, 0125 C ₂ H ₅ H (C ₂ H ₅ ) ₂ 0.003 0, 191 15th / 2

Dae review proceed η is dergegeben in Example 8 of US Patent 3,020,200 and in Example 2 of United States Patent 3 2t 1610 as. "

Bsi other experiments was the anticoccidlelle activity according to the method d © a Example 4 of US 3,211,610 certain -Patentschrift methyl-6-n "propyl-'7-diäthylaraino"4-hydroxy'-ohinolin-3-carboxylate shows the indicated below Activity:

10 9 815/2191

11191

Concentration in
putter number of
chick Mortal
speed β digit
(#) Weight *
increasing Oosysts in
survival
the birds
(Millions) Bo tenella 0.00075 20th 10 79 8.2 0.0015 20th 0 105 6.0 0.003 20th 0 96 3.2 0.006 20th 0 107 0 ₉ 1 Infected
control 120 57 48 2O ₉ O Hormones
control 40 0 100 O ₉ I. Eo maxima 0.00075 20th 0 78 1.6 0.0015 20th 0 85 0.2 0.003 20th 0 93 0.2 0.006 20th 0 105 0.1 Infected
control 12C 0 73 5.3 Normal
control 40 0 94 0.1 Bo brunetti 0.0004 10 10 83 3.4 0.00075 10 0 88 3.7 0.0015 10 0 OK4 0.1 0.003 10 0 107 0.1 infected
control 60 8th 43 18.7 Woftaale
Koafcroil © 20th ö 109 0.1

109815/2191

The following examples illustrate the invention further, without to restrict them »

B e i β ρ 1 e 1 1

Meth _l yl -'6-n '"PΓOpyl" 7 ° * diet, vlaιnilϊo ~ 4-hydroxy-quinoline- ^ 3-oarboxylate

52.3 grams of 2Ha ~ propyl ~ 5 ~ nitro-N, N-dlät hy! Aniline are hydrogenated in 500 ml of methanol in the presence of 5.5 grams of 5% pelladium aui Carbon catalyst at room temperature and under a hydrogen Overpressure of about 2.8 kg / cm, interrupted as soon as the theoretical amount of hydrogen has been absorbed, the hydrogenation * separates the The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure in an oil, which consists predominantly of 2-n-propyl-5-amino-ir, H-dlataylaniline consists; this product is used directly in the next stage without further purification

48.7 grams of the oil obtained as described immediately above 43.5 grams of bimethylraethoxyethylene malonate are added to 1 liter of toluene hinsu, keeps the vegetables refluxed for hours « conditions and as a result, under reduced pressure to remove « nuiag dee..Toluole a to a Büiiksfeaiid of 86 Graaiai des Anils « Mat hyl ~ a-carbomethoiEy-S -. (5 -diathylsfflioo ^ -n-sropyl-anllino) -aorylate au received »Biese Substans is * eo as it is, without waittra Cleaning usable

109815/2191

1500 ml Dodecylbaaaol "era ©« under Rührsii on S5O-26O heated ⁰ C York Convention during a side glitch flag TFON about 5 mewed 86 grams of Anils sugsfUgt c withdraw solution obtained is 15 bis 20 min at 250 260 ⁰ C quilted $ wa then isstttr Büferea left to cool to home temperature. The obtained synthetic material is filtered off, washed with acetone at Baiaffitssaper &tisi's and dried and then gives essentially pure methyl-6-β-propyl-7-ethylamino-4-hydroxy-quinolium-5-earbylate _$ mp. 198-204 ⁰ O. This product is dissolved in 3% dimethylformamide, treated with activated charcoal; filtered and chilled. Plltrat to 0 to 5 ⁰ C from. The product crystallizes waü wirö collected by filtration »mp * 212 ⁰ C«

A second portion obtained dur @ li Wteisrerhitzen of Dcdecylbenzolfiltrate for 15 minutes at 25 © - © 26 ⁰ C, cooled to room temperature una addition of 400 ml of acetone. The solid methyl 6-n-propyl-7-diethylamino-4-hydroxy-quinoline-3-carboxylate obtained is obtained and purified in the same manner as described above.

Example 2

oarbogylate

Map adds 7j8 GraioD diethyl thoxymethylene malonate in 200 ml toluene

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1695A06

7.5 grams of 4-n-propyl-3-diethylarainoaniline (referred to in other ways as 2-n-propyl-5-amino-N, N-diethyl aniline) are added, the mixture obtained is kept under reflux conditions for two hours, it is concentrated then in a vacuum to dryness in order to remove the solvent and the alcohol formed as the reaction product and add the residue, which consists of ethyl-cx-earboethoxy-ß- (3-diethylamioo-4-n-propyl-anilino) -acrylate, benzene to 400 ml of vigorously stirred Dodecy at 250 - 260 ⁰ C hinzu-!. The mixture is kept at this temperature for 15 minutes and then allowed to cool to room temperature. The resulting solid is separated by filtration, washed with acetone and yields 5 grams of ethyl 6-n-propyl-7 ~ diethylamino-4-hydroxy-quinoline-3-carboxylate, mp. 204-206 ⁰ C ₀

Following the above procedure using 4-n-propyl-3 ~ dimethylamine © aniline repeated as the starting material is obtained Ethy l ~ 6-n-propy 1-7 ^ 3 imethylamino ^ -hydroxy-quinoline ^ -earboxy let

Example 3 .

earboxylate

10 grams of 2 ~ 18Qbutyl-5-nitro-N _e N-diethylaniline are hydrogenated in

100 ml of methanol at room temperature About 0.7 grams of palladium-carbon

BADOR ₁₆₁ NAt _109815/2191

Catalyst under a hydrogen overpressure of about 2.8 kg / om, until the theoretical amount of hydrogen is absorbed, separates then the catalyst is removed by filtration, the mixture is concentrated in vacuo to give an oil of 4-13obutyl-3-diethylaminoaniline, adds this oil 8 grams of dimethyl methoxymethylene malonate in 200 ml of toluene to, the resulting mixture holds 90 IGn. on return flow conditions and then concentrates it to dryness in vacuo to leave a residue from methyl a ~ carbomethoxy-ß- (3-diethylamino-4-isobutyl-aniline) acrylate.

The latter substance is added directly to 300 ml Dödecylbenzol at 250 - added to 260 ⁰ C, the mixture at this temperature, stirred for 20 min, then cooled to room temperature and the resulting solid separated by filtration, washed with acetone and dried to give methyl-e-. isobutyl-T-diethylamine ^ - β-bydroxy-quinoline ~ 3 ~ earboxylate, Fpο 206-208 ⁰ O, to give.

Example 4

Methyl-6-sec »» butyl ~ 7-diethylainin-4-hydroxy-ohinoline-3 ~ oarboocylate

Following the procedure of Example 3 using 2 sec * -. Btttyl-5-nltro-H, N-diethy! Aniline repeated all starting material, receives nan Methyi-ö-seke-butyl-T-diethylaaino ^ -hydroxy-ohlßolin-

* 21 ~

109815/2191

3-earboxylate, pp. 239-243 ° Co

Example 5

Ao methyl 6 ~ n '~ butyl-7-diethylamino _r 4- hydroxyquinoline °° 3 ° carbogylate

32 grams of 2- n-butyl-5-nitro-li, li-diethylanlline are hydrogenated in 300 ml of methanol at room temperature using 2 g of 5

μ- 2

PailadiuBS-on-charcoal catalyst and under about 2.8 kg / eip hydrogen pressure, allows the hydrogenation to proceed until the theoretical Amount of hydrogen is absorbed, filtered at the end of this When the catalyst times out, the filtrate is concentrated to dryness and receives 30 grams of an oil, which mainly consists of 2-n-butyl-5-amino ~ N, N-diethylaniline consists »This material is divided into two equal parts, one for the heat of this experiment and the other for the one described in Part B below Attempt is used «,

15 grams of dimethyl methoxymethylene asalonate in 300 ml of toluene are added to 15 grams of the above product, this mixture is refluxed for 2 1/2 hours, then the toluene is removed by concentration in vacuo, the remaining anil is no longer purified, but it is added directly 250 260 ⁰ O to 500 eil Dodeoy! Benzene to. Bas Semlseh is 30 min

10S81

stirred at this temperature and then slowly cooled to room temperature. The solid product is separated by filtration, washed with acetone and dried to give 5 _t 6 g Methy1-6-n-buty 1-7-diäthylamlno ^ -hydroxy-quinolino-carboxylate, Pp. 200-205 ⁰ C.

Bo ethyl-en-butyl ^ ethylamino ^ -hydroxy-quinoline ^ - carboxylate

15 grams of the aniline derivative obtained above are reacted with dietary ethoxy methyl malonate and the anil obtained is heated in dodecylbenzene as described above to add 9-3 g of ethyl-6-n-butyl-7-diethylamino ~ 4- hyäroxy-ehinolin-3 ~ earboxylat, mp. 198-200 ⁰ C to obtain, ο

Example 6

Methyl-S-isopropyl-T-diethylamino ^ -hydroxy'-quinoline ^ - ' carboxylate

26 grams of 2-isopropyl-5-nitro-N _f N-diethylaniline are hydrogenated to 2-isopropyl-5 = amino-N _r N-diethylaniline, the last-mentioned material is reacted with 22 grams of dimethyl methoxymethylene malonate in 500 ml of toluene and the resulting anil is heated according to the method described in Example 1 in 700 ml of dodecyl benzene »by 12.3. Gram Methy 1-6-ieopropy 1 «7-diethylamino-4» hydroxy-quinoline-3-carboxylate, Pp ₀ 246-253 ⁰ C, to obtain «

.. ..., -, · ,. 109815/2191

1.1191

When performing this procedure using 2-isopropyl-5 ~ nitro ~ N, N-dimethylaniline and diethylätboxymethylenafalonat repeated p ethyl-6-18opropyl-7-dimethylamino-4-hydroxy is obtained quinoline-3-carhoxylato

Example 7

carboxylate

44 »4 grams of 2 ~ ethyl ~ 5 ~ nitro ~ K, N-diethy! Aniline are hydrogenated in 400 ml of methanol at room temperature using 2 teaspoons of Raney nickel catalyst under a hydrogen snack of about 2.3 kg / cm ² s, filtered, as soon as the hydrogen uptake is complete, the catalyst and divides the solution into two equal parts o One part is added 17.4 g of dimethyl methoxy

• Methylenmalonate to "heat the mixture for one hour on a steam bath, then the reaction mixture evaporates in a vacuum to an oil, which mainly consists of the anil methyl-α-carbomethoxy-ß-iJ-diethylamiao ^ -äthylfcanilinoJ-acrylate, this material sets directly to 500 ml Bodecy! benzene au and the mixture is heated JO min at 255 _o ⁰ Co the resulting solid is collected by filtration and recrystallized from dimethylformamide »recrystallized to substantially pure methyl

244 ⁰ C ₈ to yield

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169540b

11191 '

Β « Ethyl-S-ethyl ^ diethylamino ^ -hydrosy'-ohinolin - ^ - carboxylate

21.6 grams of ethyl ethoxymethylene malonate are added to the other half of the methanolic solution obtained above and this reaction mixture is treated as described above for ethyl 6-ethyl-7-ethyl-7-ethylaoino-4-hydroxy-ehinoline-3-carboxylate, Ρρ _β 251 ⁰ C.

Example 8

3-carbomethoxy ~ 4-hydroxy-6-n-> prbpyl-'7-quinolyl-> diethylmethyl » ammonium iodide

15 ml of methanol and 25 ml of methyl iodide are added to 2.5 grams of methyl e-n-propyl ^ -diSthylaminoM-hydroxy-ohinoline-3-earboxylate,

heat the solution obtained for 5 days under reflux conditions, then remove the solvent in vacuo and crystallize the adhesive from acetonitrile to add 1.05 grams of 3-carbomethoxy-4-hydroxy-6-n-propyl-7-ohinolyl-diethylmethyl- ammonium iodide au received; Recrystallization from acetonitrile gives essentially pure material with a melting point of 126-127 ⁰ O.

1.08815 / 2101

Example 9

Methyl 6-n-propyl-7-dlethylamino-4-hydroxy-quinoline ° -5-carboxylate

1.5 ml of concentrated sulfuric acid are added to a suspension of 0.6 grams of 6-n "propyl" -7-diethylamino-4-hydroxy- ^} hinolin-3-carboxylic acid in 20 ml of methanol and the mixture obtained is heated for 15 hours On a steam bath, then removed most of the alcohols by concentrating in vacuo, cooling the residue, neutralizing it with 10biger sodium carbonate solution, separating the resulting precipitate and recrystallizing it from dimethylformamide to give essentially pure methyl-en-propyl-diethylamino ^ -hydroxy-quinoline - ^ - earboxylate to obtain _o

Grams of 6-n ~ propyl-7 "-diethylamino-4-hydroxy-ehinoline" -3 "carboxylic acid in benzene with a molar equivalent of thionyl chloride is 7 hours » kept at reflux conditions, the acid chloride obtained was separated off and refluxed in 40 ml of methanol for 5 hours «. The reaction mixture is then filtered, the filtrate is cooled, separates the solid product and recrystallizes it from dimethylformamide to give methyl 6-δ-propyl-7-diethylamino-4-hydroxy-ehinoline-3-carboxylate to surrender

The starting materials for the production of the erfindungegemäesea

103815/2191. * "'

quinoline ~ 3-carboxylate a- 3 ~ Malkylataino-4 * -niederin © le-alkylaniline (In another way they are called 2 »HiederniQl. ~ & lkyl-5-eraißo-IT, Να ielky! aniline} of the formula

where Y _{1 is} Niedercnolο-alkyl and Yg is di-lower molo-alkylamino ο Such compounds are obtained in the catalytic hydrogenation of the corresponding nitro compounds using a palladium = or Raney nickel catalyst, ^ those nitro compounds which are not specifically in the literature are described? can be prepared according to the following process for the preparation of the starting compounds of Examples 1 to 7 above,

A solution of 54 ml (77 grams) of nitric acid (D 1.42) in 75 ml (158 grams) of sulfuric acid (B 1.84} is added dropwise with vigorous stirring to IGO grams of n-propy! Benzene over a period of about added 2 hours during the addition the temperature is maintained by means of äusaeren KUhlene at 25 -. 30 ⁰ C, stirred once the addition is complete, the mixture was further

10 9 8 15/2191

2 hours at 25 - 50 ⁰ C and then for 1 hour at 40 ⁰ C, then the mixture is poured under stirring onto crushed ice, extracted with 3 χ 75 ml hexane, combine the hexane extracts and washed successively with 50 ml portions of Y / Aaser aqueous Sodium bicarbonate, and finally again with water, the hexane solution is dried over magnesium sulfate, filtered and the hexane is removed under reduced pressure. The UI that remains is distilled using a spinning band fractionation column at reduced pressure. The desired o-isomer is the lowest-boiling isomer; it boils at 118 ° C / 15 mm and this fraction of the distillate is collected to give 2-nitro-n-propylbenzolo

Other 2-nitro-alkylbenzenes are produced in the same manner by nitration of the appropriate alkylbenzenes Examples of typical compounds show the following constants: 2-Nitro-isobutylbenzene, Kp * 124 ⁰ C / 15 mm; 2-nitro-sec-butylbenzene, b.p. 122 ° C / 13 mm; 2-Kitro-n-butylbenzene, b.p. 132 ° C / 14 mm; 2-Nitro-isopropylbenzene, Kp ₀ 115 ° C / 15 RAM.

Bo 2-n-propyl-NN-diethy! Aniline » 79 grams of 2-nitro-n-propylbenzene in 600 ml of absolute ethanol and 64 ml of acetaldehyde are treated in the presence of 5 grams of 5% palladium-on- ⁷ hle catalyst at room temperature and hydrogenated under a hydrogen pressure of about 2.8 kg / cm ² . As soon as the hydrogen uptake stops (in the

10 98 15/2191

look for the presence of excess acetaldehyde a larger than the theoretical amount absorbed), separates the catalyst is removed by filtration and the alcohol is removed under reduced pressure «The residue is distilled under reduced pressure and yields 2 ~ n-propyl-N, N-dlethylaniline, Kpc 127 - 133 ° C / 28 mm »

Other 2-alkyl-H N-diethy / anilines, which are prepared in the same way, show the following properties: 2-isobutyl-N, N-diethy / aniline, b.p. 124-127 ° C / 25 mm; 2-sec-butyl-N, N ~ diethylaniline, b.p. 129 ° C / 25 mm; 2-n-butyl-N, N-diet hy! Aniline, Kpo 143 ° C / 29 MMJ 2-Ioopropyl-N, N-diäthy! Aniline, Kp, 126 ⁰ C / 28 mm "■■

The use of formaldehyde or propionaldehyde instead of Acetaldehyde gives the corresponding Ν, Ν-dimethyl- or N, N-dipropy! Aniline ο

Another method, such as is used for the preparation of 2-ethyl ~ N, N-diethylaniline let, the nachstehendet A mixture of 100 g of 2-ethylaniline and 150 g of triethyl phosphate and heated to about 160 ^Q C 'As soon as the exothermic reaction nachläset, the mixture is stirred and heated for 4 hours at 200 ⁰ C, "the mixture is cooled and carefully etched him a LUsung of 100 g of sodium hydroxide in SOQ ml Waeeer bu,

^: " ^{: i <} 109815/2191

stir the mixture for 12 hours at room temperature, extract the precipitated oil in ether, then dry the ether extracts, evaporated to dryness and the residue was distilled at atmospheric pressure. The at. The fraction distilling at 220 ° C is 2-ethyl ~ N, N-diethy! Aniline.

74 g of 2-n-propyl ~ N, H <= diethylaniline are added to 400 ml of sulfuric acid (D 1.84) with stirring and cooling, the temperature being kept below 20 ^° C. during this addition, then the solution is cooled 0 ^° C. and a solution of 20 ml of nitric acid (D 1.42) in 60 ml of sulfuric acid (D 1.84) is added dropwise, keeping the temperature at 0 to 5 ^° C. As soon as the addition is complete, the mixture becomes stirred for a further 30 minutes at 5 ⁰ O and then poured on ice, the mixture is neutralized by addition of solid sodium carbonate "During the addition is to be small amounts of ether in order to keep the foaming under control. After neutralization, ate mixture is brought to room temperature (in order to dissolve the faydratiaierte sodium sulfate) and extracted with 100 ml of ether. The ether extracts are combined, washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. The residue is distilled under reduced pressure and gives 2-nI> ropyl-5-nitro-N, N-diethy / aniline, boiling point 134 ° O / 1.8

T 0 9 815/2191

30 -

Other 2-alkyl-5-nitro-N, N-di-lower molar -alkylanilines are prepared from the corresponding starting materials in the same way, examples of which are: 2-isobutyl-5-nitro-N, N- diethylaniline, b.p. 134-155 ° C / O, 75-1.0 mm; 2-sec-butyl- = 5-nitro-'N, N-diethylaniline, b.p. ₀ 135 ⁰ C / 1 »3 mm} 2-n _{-butyl-5-nitro-N, N = 4-diethylaniline, b.p. D} H 3 ° C / 1 ₉ 65 mm; 2 ~ isopropyl "5-nitro-.H _f N-diethylaniline, Kp ₀ 124 ° C / 1.45 mm and 2" Ethyl 5-nitro-N, li-äiäthylanilin, bp. 126 ° C / 0 5 _f

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Claims (1)

M 75 481 IY d / 12 ρ Merck & Co. » Soft. 11 191 New Claims 1. Compounds of the general formula where R · nledermol «alkyl, Rg nledermol. Alkyl with 2 to Carbon atoms and R, di-lower molar-alkylamino represent » 2. Compounds according to claim 1, characterized in that R, Means methyl or ethyl. 5. Methyl-ö-n-propyi-T-diethylamino - ^ - hydroxy-quinoline-J-carboxylato 4. Ethyl-6-n-propyl-7-diethylamino-4-hydroxy-quinoline-5- carboxylato 5. Methyl 6-n-butyl-7 ° diXthylailno-4-hydroxy-ohinoln-3-carboxylate. ^ ue Untertaen (Article 7 si Para.? Nr.ι sat 3 «» ΟWt ^ rf ^ * ».> .- f. ^ rl > / Qaaternary salt of a compound of the formula OH wherein R is nledexnol. Alkyl, Ig niedexmol «alkyl with 2 to 4 carbon atoms and fU SH> nledermol · alkylamlno mean. 7 »Process for the preparation of compounds according to Claim 1, dadurafo gskennzeiehsiefe that one can obtain a compound of the general formula. . COOR, where R, Rg and R ^ have the meaning given in claim 1, heated, or that one converts the corresponding quinol carbonic acid or its acid chloride in a manner known per se into the lower alkyl alkyl ester, 8. The method na @ h claim 7, characterized in that one elnüsfezit a compound, in which Ry is methyl or ethyl, Rg is n-Propyi and R _{7 is} diethylamine. 1098 15/2191