United States Patent 0 M
`1C6
`
`3,297,525
`Patented Jan. 10, 1967
`
`1
`
`3,297,525
`FUNGICIDAL COMPOSITIONS COMPRISING
`SALICYLATES OF 8 HYDROXY QUINOLINE
`CARBOXYLIC ESTERS
`Nathaniel Grier, Englewood, N.J., assignor, by mesne as
`signments, to Merck & Co., Inc., Rahway, N.J., a cor
`poration of New Jersey
`No Drawing. Filed Oct. 19, 1962, Ser. No. 231,813
`22 Claims. (Cl. 167-—58)
`
`2
`product resulted in excellent yield and of a composition
`corresponding to one molecule of salicylic acid for each
`molecule of 8-quinolinylbenzoate. This was all the more
`unexpected as under the same conditions phthalic acid,
`which is the corresponding o-carboxylic benzoic acid, and
`is comparable to salicylic acid in acid strength
`
`failed to form a salt.
`A possible explanation for the unusual and unexpected
`results obtained, although it is to be understood that I am
`not committed to such theory, may be in terms of a two
`fold joining of the reactants, on the one hand, by typical
`salt formation between the carboxylic acid and the basis
`heterocyclic nitrogen together with intermolecular hydro
`gen bonding of the ortho hydroxyl hydrogen with the
`carbonyl of the ester carboxylate, on the other, to give
`a stable compound, viz:
`
`10
`The present application is a continuation-in-part of my
`copending application Serial No. 758,555, ?led September
`2, 1958.
`The present invention relates to the manufacture of new
`compounds and compositions containing the same char
`acterized by a high antifungal and antibacterial activity
`and suitable for clinical and industrial use.
`It is the general object of the invention to provide im
`proved compounds and compositions possessing powerful
`antimicrobial activity and capable‘ of use both clinically
`for the treatment of fungal infections, as against the or
`ganisms causing dermatophytosis pedis (“athlete’s foot”),
`and industrially, as in the mildewproo?ng of paints and
`other coating compositions and organic ?lms of various
`kinds subject to fungal action, impregnating compositions,
`and for disinfection generally.
`It is a particular object of the invention to provide anti
`fungal agents which in clinical use are substantially free
`from irritation, are rapid and reliable in their action, and
`promote rapid healing of diseased areas of long standing.
`Other objects and advantages of the invention will become
`apparent from the detailed description hereinafter.
`Brie?y described, the invention relates to antifungal and
`antibacterial agents obtained by the reaction of esters of
`S-hydroxyquinolines with salicylic acids, the products
`being in thenature of addition compounds or “salts.”
`It is well known that 8-hydroxyquinolines form addi
`tion compounds or amine salts with a wide variety of in—
`organic and organic acids. Included among the latter are
`malonic, maleic, succinic, citric, tartaric, phthalic, salicyl
`ic, and beta-resorcylic acids. Also, many esters of S-hy
`droxyquinolines have been synthesized. However, al
`though some of these esters have been used to form salts
`with inorganic and certain sulfonic acids, they can not be
`converted into the salts of the common organic acids.
`Thus, the benzoic ester of S-hydroxyquinoline has been
`synthesized using known procedures, but attempts by me'
`to prepare salts of this ester with such acids as malonic,
`maleic, citric, tartaric and phthalic were unsuccessful. In
`50
`each case there was no reaction of the components when
`used in either equivalent or molar excess proportions in >
`'
`homogeneous solutions in various solvents, e.g., aqueous
`alcohols, anhydrous alcohols, ether, benzene, chloroform,
`etc. In every instance the -8-quinolinyl benzoate base was
`recovered in almost quantitative yield after each trial.
`Under the same conditions, S-hydroxyquinoline itself
`readily forms salts with these acids, the products being
`well de?ned and isolatable. However, S-quinolinylben
`zoate failed to form a salt even with so acidic a substance
`as o-sulfobenzimide (KA=2.5 X 10-2). Attempts to com
`bine phthalic acid- with 8-quinolinylbenzoate yielded
`nothing but the original reactants.
`Similar results were obtained with ?-resorcylic acid
`(2,4-dihydroxybenzoic acid) and gentisic acid (2,5-dihy
`droxybenzoic acid). Although these two latter acids
`form salts readily with S-hydroxylquinoline, they failed
`to react with 8-quinolinylbenzoate.
`It was accordingly most surprising to discover that when
`S-quinolinylbenzoate (and also other esters, and of further
`substituted quinolines, as described below) was reacted
`with o-hydroxybenzoic acid (salicylic acid) a well-de?ned
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`Mere hydrogen bonding can not bring about a stable
`linkage as shown by the failure of the attempt to effect
`a reaction between l8-quinolinylbenzoate with ortho nitro
`phenol. No addition took place under a variety of ex
`perimental conditions. The highly speci?c properties
`needed for reaction were demonstrated by the failure of
`ethylene diamine tetra-acetic acid to give an isolatable re
`action product with v8-quinolinyl benzoate when used in
`equimolecular proportions employing solutions prepared
`from formamide and water. Even thiosalicylic acid, i.e.,
`ortho mercaptobenzoic acid, was recovered unchanged
`when equivalent proportions or even excess amounts were
`mixed in a variety of solvents with the above-named ester.
`Although a strong similarity exists between salicylic acid
`and its sulfur analog, it is possible that the mercapto hy
`drogen is too tightly held by the sulfur, thus preventing
`intermolecular hydrogen bonding. Salicylic acid substi
`tuted with groups containing additional acidic hydrogen
`atoms, e.g. ?-resorcylic and gentisic acids, showed no re
`activity, and in these instances it is possible that the avail
`able acidic hydrogen of the hydroxyl distant from the
`salt-forming carboxyl preferentially interfered with hy
`drogen bonding of the ortho hydroxyl hydrogen.
`The compounds of the present invention are accordingly
`comprised within the following general formula:
`
`55
`
`60
`
`wherein Y is the 8-quinolinyl radical or a substituted 8
`quinolinyl radical while R is the residue of a monobasic
`or dibasic aliphatic, or also of an aromatic or hetero
`cyclic acid, and X is a phenyl radical free from substit
`uents containing additional acidic hydrogen atoms. Thus
`R may be an alkyl or substituted alkyl group having up
`to 18 carbon atoms, and may also be aryl, aralkyl, aralkyl
`ene, furyl, and the like. By way of example, the salts of
`the invention include the salicylic acid salts of 8-quino
`linyl acetate, propionate, butyrate, t-butyl acetate, lau
`rate, pahnitate, stearate, cyclohexyl and cyclopentyl ace
`tate and propionate, benzoate, cinnamate, phenyl acetate
`and propionate, veratrate, furoate, and also the di-salicylic
`acid salts of di-8-quinolinyl phthalate and iso-phthalate,
`di-S-quinolinyl malonate and di-B-quinolinyl succinate.
`70
`For example, a new ester, di-S-quinolinyl phthalate,
`‘was prepared from phthalyl chloride and 8-hydroxy
`
`CFAD Exhibit 1022
`
`1
`
`

`
`3,297,525
`
`3
`quinoline in pyridine. Even when the phthalyl chloride
`was used in large excess and the 8-hydroxyquinoline
`added gradually to it, the only product obtained was the
`di-ester of 8-hydroxyquinoline and phthalic acid. This
`ester upon reaction with salicylic acid yielded a product 5
`which analyzed correctly for the composition
`C26H1504N2 · 2C7H60s
`molecular weight 696, corresponding to the structural
`formula
`
`Q
`
`on coon
`
`,~
`
`0/8-o-O
`" -g
`I 0
`
`C-0
`II
`0
`
`/
`N~
`
`on coon
`I
`
`4
`orine, chlorine and bromine, but preferably iodine), nitro,
`and the like. Examples of such salicylic acids are:
`5-chlorosalicylic acid, 3,5-diiodosalicylic acid, 4-methyl
`salicylic acid, 3-hexyl and 3-cyclohexyl salicylic acid, 3-
`phenylsalicylic acid, and 3,5-dinitrosalicylic acid. These
`acids can be used to form salts with any of the esters of
`8-hydroxyquinolines named herein.
`Both the quinoline and salicylic nuclei of any salt can
`be further substituted as above described. Moreover, the
`10 alkyl, aryl or heterocyclic radicals of the ester groups can
`be substituted by halogen or nitro in the case of the alkyl
`radicals, or by halogen, lower alkyl or nitro in the case
`of cyclohexyl, aromatic or heterocyclic carboxylic acids.
`Examples of these are the salicylates (unsubstituted or
`15 substituted as above described) of p-chloro cyclohexyl
`carboxylic acid ester of 8-hydroxyquinoline, the p-nitro(cid:173)
`benzoic acid ester, the alpha-nitrofuroic acid ester, the
`o-ethyl and o-chloro-benzoic acid ester, the 2-chloro-
`propionic acid ester, and the like.
`The compounds of the invention are accordingly em(cid:173)
`braced by the foilowing general formula:
`
`20
`
`25
`
`30
`
`45
`
`The compound is thus composed of one molecule of
`di-8-quinolinyl phthalate and 2 molecules of salicylic
`acid. Attempts to prepare the product corresponding to
`one molecule of di-8-quinolinyl phthalate and one mole(cid:173)
`cule of salicylic acid by the use of an excess of the di-8- 35
`quinolinyl ester were unsuccessful; only the above product
`was obtained.
`This reaction was extended to a variety of esters of 8-
`hydroxyquinoline. For example, 8-quinolinyl cinnamate, 40
`phenylacetate, butyrate, laurate, and palmitate formed
`isolatatable, weII-defined products when reacted with
`salicylic acid.
`The high degree of anti-fungal effectiveness and sub(cid:173)
`stantial freedom from irritation of the salicylate salts of
`the present invention (as described more fully hereinbe(cid:173)
`low) are also most surprising in view of the fact that
`salicylic acid, both alone and mixed, as in Whitfield's
`Ointment, has practically no antifungal power, its action
`being "due chiefly to its keratolytic effect, and it is highly 60
`irritating" ("Antiseptics, Disinfectants, Fungicides and
`Sterilization," edited by G. F. Reddish, Lea & Febiger,
`Philadelphia, 1954, pp. 557-8).
`The quinoline ester can be nuclearly further substituted
`by one or more groups free of acidic hydrogens, like 65
`halogen (fluorine, chlorine, bromine and iodine), lower
`alkyls (up to eight carbon atoms), nitro, and the like.
`Thus in place .of 8-hydroxyquinoline (in the formation of
`the ester) there may be employed 5-chloro-7-iodo-8-
`hydroxyquinoline, 5,7,-diiodo-8-hydroxyquinoline, and 5, 60
`7-dibromo-8-hydroxyquinoline.
`The salicylate salts, including the salt of salicylic acid
`itself, of the esters, such as the benzoic acid ester, of
`these dihalogenated 8-hydroxy-quinolines, are more effec(cid:173)
`tive and less irritating in the treatment of microbially in- 65
`duced pathologic conditions than the known diiodo-8-
`hydroxyquinoline.
`The quinoline nucleus may also be both halogenated
`and alkylated, examples of such compounds being the
`salicylic acid salts of the benzoic acid esters of 3-methyl- 70
`5-chloro-7-iodo-8-hydroxyquinoline and 4-methyl-5,7-di(cid:173)
`bromo-8-hydroxyquinoline, and the like.
`The phenyl nucleus of the salicylic acid can be similar-
`ly further substituted by groups free from acidic hydrogen,
`including lower alkyl, cyclohexyl, phenyl, halogen (flu- 75
`
`wherein
`R is the residue of an organic monocarboxylic acid, or of
`an organic polycarboxylic acid whose other carboxyl
`group or groups (as in the case of citric acid) are es(cid:173)
`terified with an 8-hydroxyquinoline similarly salified
`with a salicylic acid, such residue being further sub(cid:173)
`stituted or not, as with halogen, nitro, lower alkyl and
`.other groups free of acidic hydrogen;
`Rl and R2 are hydrogen, halogen (any of the four, but
`preferably iodine), lower alkyl (e.g., 3 and/or 5-
`methyl), nitro, or other group devoid of acidic hydro(cid:173)
`gen;
`Xis hydrogen or lower alkyl;
`Y and Z are hydrogen, halogen, nitro, or other groups
`having no acidic hydrogen.
`The following examples illustrate detailed procedures
`for the preparation of the compounds of the invention,
`but are not to be understood as indicating the scope
`.thereof.
`
`EXAMPLE 1
`8-quinolinyl benzoate-salicyllic acid salt
`124 grams 8-quinolinyl benzoate (M.P. 123-124° C.)
`and 70 gms. salicylic acid were dissolved in 1200 ml.
`99% isopropyl alcohol by heating and stirring. On slow
`cooling thick colorless needles graduaIIy formed. After
`12 hours the product was removed by suction filtration,
`washed with 99% isopropyl alcohol, and air-dried. The
`yield was 130 grams of a colorless product.
`For analysis a sample was recrystallized from 99%
`isopropyl alcohol, M.P. 135.6-136.6° (Anschiitz ther(cid:173)
`mometer). Carbon, hydrogen and nitrogen values were
`in exceIIent agreement for the composition,
`Cl6H1102N.C7HGOa
`
`mol. wt. 387.
`The specificity of this reaction in terms of the acid used
`is illustrated by the following:
`6.2 gms. 8-quinolinyl benzoate and 2.9 gms. maleic
`acid were dissolved by warming in 65 ml. 99% isopropyl
`alcohol to give a clear solution. On slow cooling, large
`colorless prisms formed; after standing, these were re(cid:173)
`covered by suction filtration, :washed with 99% isopropyl
`alcohol and dried. The first crop yielded 5.04 gms.,
`
`2
`
`

`
`5
`M.P. 123-124° C. A mixed melting point and analysis
`showed this product to be unreacted 8-quinolinyl benzo(cid:173)
`ate. Concentration of the :filtrate yielded the remainder
`of the 8-quinolinyl benzoate in an uncombined state.
`This experiment was repeated using the same ester
`with different mganic carboxylic acids, e.g., phthalic,
`malonic, succinic, tartaric, thiosalicylic, beta-resorcylic,
`gentisic and others. The solvents used were chosen on
`the basis of providing mutual solubility, secondary alco(cid:173)
`hols being preferred over primary to avoid ester exchange.
`In all these instances the 8-quinolinyl benzoate was re(cid:173)
`covered uncombined in high yield. o-Sulfobenzimide
`dissolved in 99% isopropyl alcohol together with an
`equivalent amount of 8-quinolinyl benzoate also failed
`to react.
`
`3,297,525
`
`6
`the product was filtered, washed with benzene and air(cid:173)
`dried. Yield 12 gms. of colorless crystals. This was re(cid:173)
`crystallized from benzene, M.P. 140-142 ° C. (Anschlitz
`therm.). Analysis for carbon, hydrogen and nitmgen
`5 gave excellent agreement
`for C26H 160 4N2.2C7H503,
`molecular weight 696.
`Attempts to prepare the mono salicylic acid reaction
`product with the di-8-quinolinyl phthalate by the use of
`equi-molar proportions were unsuccessful, the di-salicylic
`10 acid-Oi-8-quinolinyl phthalate being the only isolatable re(cid:173)
`action product.
`
`EXAMPLE 3
`
`EXAMPLE2
`Di~8-quinolinylphthalate-di-salicylic acid salt
`(a) Di-8-quinolinyl phthalate.-30 gms. (0.21 mole)
`8-hydroxyquinoline were dissolved in 120 gms. anhydrous
`pyridine in a 500 ml. 3-neck round bottom flask equipped
`with a thermometer, dropping funnel, agitator, cooling
`bath, and vented to the atmosphere through a calcium
`chloride drying tube. The internal temperature was
`maintained at 10 to 15° C. and over a period of 1~
`hours there were then added dropwise 25 gms. (0.12
`mole) phthalyl chloride. After complete addition, the
`mixture was agitated an additional 1 ~ hours at 15 to
`20° C. It was then poured into 500 ml. water, stirred
`thoroughly and allowed to stand overnight. The small ex- 30
`cess of phthalyl chloride which remained was thus con(cid:173)
`verted to phthalic acid, and this remained in solution as
`the pyridine salt. The di-8-quinolinyl phthalate was re(cid:173)
`moved by suction filtration, washed well with water, and
`air-Oried at room temperature. A yield of 35 gms. 35
`80% was obtained. The product was crystallized
`from benzene (35 gms. in 400 ml.) to give large, colorless
`prisms, melting point 178-180° C. to a clear colorless
`melt. Analysis for carbon, hydrogen and nitrogen con(cid:173)
`.firmed the composition C26H 160 4N2, molecular weight 40
`420.
`Di-8-quinolinyl phthalate is colorless, odorless, poorly
`soluble in water, and slightly soluble in methyl or 99%
`isopropyl alcohol. On boiling a suspension of the prod-
`uct in water, no color is observed. Testing of the liquor 45
`rwith ferric chloride showed that no 8-hydroxyquinoline
`had been liberated. However, di-8-quinolinyl phthalate
`is readily soluble in dilute aqueous hydrochloric acid and
`on heating, rapid hydrolysis results; the thus-formed 8-
`hydroxyquinoline hydrochloride causing a strong yellow 5o
`In water made alkaline by the addition of
`coloration.
`monoethanolamine,
`the di-8-quinolinyl phthalate was
`stable even at the boiling point.
`c-- The use of the above preparative pmcedure gives rise
`to only one product, di-8-quinolinyl phthalate, even under 55
`conditions that should favor the formation of mono-8-
`quinolinyl acid phthalate. In a similar experimental set-
`up there were placed 250 gms. anhydrous pyridine into
`the reaction flask. After cooling to 15° C., 50 gms.
`(0.25 mole) phthalyl chloride were added slowly. Next, 60
`over a ~ hr. period, a solution of 20 gms. (0.14 mole)
`8-hydroxyquinoline dissolved
`in 50 gms. anhydrous
`pyridine was added. The reaction mixture rwas stirred an
`additional two hours at 15° C., quenched in 1 liter water
`and processed as before. A white crystalline powder was 65
`obtained, 28 gms., rwhich on recrystallization from ben(cid:173)
`zene had a melting point of 178-180° C. A mixed melt-
`ing point with di-8-quinolinyl phthalate was unchanged.
`The theoretical yield for this product is 29 gms.
`(b) Di-8-quinolinylphthalate-di-salicylic acid salt.- 70
`8.4 gms. (0.02 mole) di-8-quinolinyl phthalate were di~
`solved in 150 ml. boiling benzene. To this there were
`added 5.5 gms. (0.04 mole) salicylic acid. A clear solu(cid:173)
`tion resulted. On cooling and scratching a white crystal(cid:173)
`line precipitate was obtained. After standing 2 hours, 75
`
`15
`
`8-quinolinyl butyrate-salicylic acid salt
`2.76 gms. (0.02 mole) salicylic acid and 4.3 gms. (0.02
`mole) 8-quinolinyl butyrate were dissolved in mo ml.
`petroleum ether (boiling point range 30-60° C.). On
`cooling to room temperature, no precipitate formed.
`However, on refrigeration at 0° C. long, colorless need-
`20 les result; these were removed by suction :filtration,
`washed with cold :petroleum ether, and air-Oried to give
`3.0 gms. of product. Recrystallization from petroleum
`ether gave a colorless crystalline product which melted at
`77.0-77.5° C. (Anschlitz therm.) and ·analyzed correctly
`25 for CiaH130 2N.C7H503.
`EXAMPLE 4
`8-quinolinyl palmitate-salicylic acid salt
`3.8 gms. (0.01 mole) 8-quinolinyl palmitate and 1.4
`gms. {0.01 mole) salicylic ·acid were dissolved in 50 ml.
`99% isopropyl alcohol by warming. On cooling, no
`product precipitated. · The volume was reduced to 25
`ml. under vacuum, and on cooling, long colorless needles
`formed. These were removed by suction filtration,
`washed with a small volume of cold 99% isopropyl al(cid:173)
`cohol, and air-dried. The first crop of product was 3.4
`gms. For analysis this was -recrystallized from 99%
`isopropyl alcohol to give long, colorless needles, melting
`point 66.5 to 67 .2 ° (Anschlitz thefm. of the compositioq
`C25Ha102N · C7H60a, molecular weight 521.
`EXAMPLE 5
`3-methyl-8-quinolinyl benzoate-salicylic acid salt
`(a) 3-methyl - 8-quinolinyl benzoate.-Ten gms. 3-
`methyl-8-hydroxyquinoline and 20 gms. benzoyl chloride
`were mixed together and heated in an oil bath to an
`internal temperature of 170° C. for 8 hours. The molten
`reaction mass was poured into a dish, allowed to solidify,
`and then mixed with 100 ml. water for 4 hours. The
`pmduct was removed by suction filtration, washed with
`a small volume of 0.5 N HCl solution and air-dried. A
`yield of 11.0 gms. 3-methyl-8-quinolinyl benzoate was
`obtained. For analysis a sample was recrystallized from
`diethyl ether to give thick colorless prisms, M.P. 108.5-
`1090 C. (Anschlitz thermometer). Analysis for carbon,
`hydrogen, and nitrogen gave excellent checks
`for
`C11Hrn02N, mol. wt. 263.
`(b) 3-methyl - 8-quinolinyl benzoate-salicylic acid
`salt.-0.66 gm. salicylic acid was added to a clear solu(cid:173)
`tion of 1.20 gms. 3-methyl-8-quinolinyl benzoate in 30
`ml. benzene. On slow cooling, colorless crystals formed.
`These were removed by suction :filtration, washed with
`cold benzene, and air-dried. For analysis a sample was
`recrystallized from benzene, M.P. 140-141 ° C. (Ans(cid:173)
`chlitz therm.). Analysis agreed well for C24H 190 5N, mol.
`wt. 401.
`
`EXAMPLE6
`4-methyl-8-quinolinyl benzoate-salicylic acid salt
`(a) 4-methyl - 8-quinolinyl benzoate.-Ten gms. 4-
`methyl-8-hydroxyquinoline were dissolved in 40 gms.
`anhydrous pyridine. This was cooled to 10 ° C. and
`with good agitation then were added 10 gms. benzoyl
`chloride over a 1 ~ hr. period. After complete addition
`
`3
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`

`
`3,297,525
`
`7
`the temperature was then maintained at 12-14 ° C. for
`an additional hour. The solution was poured into 200
`ml. H20, stirred for I/z hr., the product suction-filtered,
`water-washed and air-dried. The yield was 15.5 gms.
`13.5 gms. were dissolved in 650 ml. mineral spirits with 5
`heating, filtered free of a slight residue and allowed to
`crystallize with slow cooling. Colorless crystals of 4-
`methyl-8-quinolinyl benzoate were obtained. For anal(cid:173)
`ysis a sample was recrystallized from mineral spirits,
`M.P. 123-124.2° C. (Anschi.itz thermometer). A mixed
`melting point with 4-methyl-8-hydroxyquinoline showed
`a large depression, as did also the mixed melting point
`with benzoic acid. Analysis confirmed the composition
`C11H130 2N, mol. wt. 263.
`(b) 4-methyl - 8-quinolinyl benzoate-salicylic acid 15
`salt.-Two gms. of 4-methyl-8-quinolinyl benzoate and
`1.1 gms. salicylic acid were dissolved in 120 ml. mineral
`spirits with heating. On slow cooling, a crystalline prod-
`uct resulted; this was separated using suction-filtration,
`washed with a small volume of mineral spirits and air- 20
`dried to give a yield of 2.9 gms. A sample for analysis
`was obtained by recrystallization from mineral spirits to
`give a practically colorless, crystalline material, M.P.
`107.5-109° C. (Anschutz thermometer), the analysis
`agreeing well with the composition C 24H 190 5N, mol. 25
`wt. 401.
`
`IO
`
`EXAMPLE 7
`8-quinolinyl benzoate-3,5-dinitrosalicylic acid salt
`2.46 gms. (0.01 mole) 3,5-dinitrosalicylic acid were 30
`dissolved in 25 ml. 99% isopropyl alcohol at room tem(cid:173)
`perature. The solution was added rapidly with stirring
`to ,a hot solution of 2.49 gms. (0.01 mole) 8-quinolinyl
`lbenzoate in 60 ml. 99% isopropyl alcohol. There was
`immediate precipitation of a yellow crystalline product. 35
`After cooling it was removed by suction filtration, washed
`with 99% isopropyl alcohol and air-dried. Yield 4.7
`gms. of yellow needles.
`For analysis 1 gram was recrystallized from 350 ml.
`99% isopropyl alcohol to give thin long yellow needles, 40
`M.P. (Anschutz therm.) 198-200° C. to a yellow liquid.
`Analysis for carbon, hydrogen, and nitrogen checked well
`for the composition C 16H110 2N ·C7H 40 7N 2, mol. wt. 477.
`EXAMPLE 8
`8-quinolinyl benzoate-3,5-diiodosalicylic acid salt
`7.8 gms. (0.02 mole) 3,5-diiodosalicylic acid were dis(cid:173)
`solved in 400 ml. boiling benzene. To this were added
`4.58 gms. (0.02 mole) 8-quinolinyl benzoate. A clear
`solution resulted which on slow cooling gave rise to color(cid:173)
`less needles. After 12 hours' standing the product was
`removed by suction filtration, washed with benzene and
`air-dried. Yield 7.0 gms. A second crop of colorless
`fiat needles weighing 3.0 gms. was obtained by concentra- 55
`tion of the above filtrate. For analysis a sample was
`recrystallized from benzene, M.P. 175.0-175.5° C.
`(Anschutz therm.). Carbon, hydrogen, and iodine values
`were in good agreement for C16H110 2N ·C7H 403l2, mol.
`wt. 639.
`
`8
`EXAMPLE 10
`Di-8-quinolinyl phtlzalate-di-3,5-diiodosalicylic
`acid salt
`7.8 gms. (0.02 mole) 3,5-diiodosalicylic acid were first
`dissolved in 400 ml. boiling benzene. To the resulting
`clear solution there were added 4.2 gms. (0.01 mole) di-
`8-quinolinyl phthalate. The clear, pale yellow solution
`was cooled, a white crystalline precipitate being obtained
`and removed using suction filtration, followed by benzene
`washing and air-drying. This yielded 10.2 gms. of prod(cid:173)
`uct and recrystallization from benzene yielded colorless
`needles, M.P. 179.2-180.8° C. (Anschutz therm.). Anal(cid:173)
`ysis for carbon, hydrogen, iodine agreed for the com(cid:173)
`position C26H 160 4N2.2C7H40 3I 2, mol. wt. 1189.6.
`EXAMPLE 11
`8-quinolinyl cinnamate-3,5-diiodosalicylic acid salt
`5.52 gms. 8-quinolinyl cinnamate were added to a boil(cid:173)
`ing solution of 7.8 gms. 3,5-diiodosalicylic acid in 400 ml.
`benzene. The solution was filtered to remove a small
`amount of brownish impurity. On cooling a colorless
`product resulted. This was isolated as described pre(cid:173)
`viously to give 3.5 gms. of product. A recrystallized
`sample (from benzene) had a melting point of 144.5-
`1460 C. (Anschtitz therm.) and analyzed correctly (car(cid:173)
`bon, hydrogen and iodine) for C18H 130 2N.C7H403I 2,
`molecular weight 664.8.
`EXAMPLE 12
`8-quinolinyl phenylacetate-3,5-dinitrosalicylic acid salt
`4.2 gms. (0.02 mole) 8-quinolinyl phenylacetate were
`dissolved in 150 ml. 99% isopropyl alcohol at the boiling
`point. To this there was added a solution of 4.9 gms.
`(0.02 mole) 3,5-dinitrosalicylic acid in 50 ml. 99% iso(cid:173)
`propyl alcohol. Rapid precipitation of a yellow solid
`resulted. After cooling to room temperature the product
`was filtered, washed with 99% isopropyl alcohol and air-
`dried. The yield was 7.2 gms. Recrystallization from
`dioxane gave fiat orange plates, M.P. 240-241 ° C.
`(Anschiitz therm.) to a red liquid. Analysis was correct
`for the composition C17H130 2N.C7H 40 7N 2, molecular
`weight 491, based on carbon, hydrogen, and nitrogen
`45 determinations.
`
`EXAMPLE 13
`8-quinolinyl butyrate-3,5-dinitrosalicylic acid salt
`2.46 gms. (0.02 mole) 3,5-dinitrosalicylic acid were
`dissolved in 25 ml. 99% isopropyl alcohol followed by
`2.15 gms. (0.02 mole) of 8-quinolinyl butyrate. A clear
`solution resulted, and a yellow product precipitated
`shortly after mixing. A total of 4.4 gms. was thereby
`recovered which after recrystallization from dioxane gave
`fine yellow needles, melting point 172-172.5° C. (An(cid:173)
`schutz therm.) and easily distinguishable from 3,5-dinitro(cid:173)
`salicylic acid by its poor water solubility. This product
`analyzed in close agreement for C13H1302N.C7H407N~,
`molecular weight 443.
`EXAMPLE 14
`8-lauroyloxyquinoline-3,5-diiodosalicylic acid salt
`3.27 g. (0.01 mole) 8-lauroyloxyquinoline (mol. wt.
`327) was dissolved in 50 ml. of boiling benzene. To this
`65 there was added a solution of 3.9 g. (0.01 mole) 3,5-di(cid:173)
`iodosalicylic acid in 200 ml. hot benzene. The two solu(cid:173)
`tions were mixed hot to give a clear amber solution
`which cooled slowly and gave rise to a small amount of
`yellowish amorphous precipitate. This was suction fil-
`70 tered, benzene washed, and air-dried 0.8 g.
`The filtrate and wash were evaporated in vacuum to 50
`ml. The resultant precipitate was suction-filtered, washed
`with a small amount of benzene followed by acetone in
`which 3,5-diiodosalicylic acid is extremely soluble. 4.4
`75 g. of colorless solid (M.P. 113-114°) was obtained. A
`
`50
`
`60
`
`EXAMPLE 9
`8-quinolinyl benzoate-3-phenylsalicylic acid salt
`5.0 gms . .(0.02 mole) 8-quinolinyl benzoate and 4.3
`gms. (0.02 mole) 3-phenylsalicylic acid were dissolved
`in 65 ml. boiling 99% isopropyl alcohol to give a com(cid:173)
`plete solution. Large, colorless prisms resulted on cool(cid:173)
`ing. These were removed by suction-filtration, washed
`with 99% isopropyl alcohol and air-dried. The yield
`was 8.2 gms. A 1-gram sample was recrystallized from
`10 ml. 99% isopropyl alcohol, giving large prisms, M.P.
`149-150° C. (Anschutz therm.). Carbon, hydrogen, and
`nitrogen values agreed for the composition
`C15H1102N ·C13H1003
`
`mol. wt. 463.
`
`4
`
`

`
`3,297,525
`
`IS
`
`10
`7-iodo-8-benzoyloxyquinoline were dissolved in a boiling
`solution of 5 ml. benzene and 15 ml. 99% isopropyl al(cid:173)
`cohol. There were then added 4.8 gms. of 3,5-diiodosal(cid:173)
`icylic acid. On slow cooling slightly green colored crys-
`tals were obtained in a yield of 6.6 gms. A sample was
`recrystallized twice for analysis from the same 3 : 1 iso(cid:173)
`propyl alcohol:benzene solution to give practically color(cid:173)
`less crystals, M.P. 171-173° C. wivh prior softening at
`168° C. (Anschutz therm.). This analyzed correctly for
`10 carbon, hydrogen, nitrogen, chlorine and iodine for the
`composition, C16H90 2NICI.C7H40 3I2, molecular weight
`799.3.
`
`9
`sample was recrystallized from benzene, using 1 g./5 ml.,
`M.P. 117.8-118.3° (Anschlitz thermometer). Carbon,
`hydrogen, and iodine analyses checked for the composi(cid:173)
`tion, C21H290 2N.C7H40 3I2, mol. wt. 716.8.
`EXAMPLE 15
`8-quinolinyl benzoate-5-clzlorosalicylic acid salt
`IO.O gms. 8-quinolinyl benzoate were dissolved in 100
`ml. 99% isopropyl alcohol at the boiling point. To this
`were added 7.0 g. 5-chlorosalicylic acid; on stirring a
`clear dark brown solution resulted. This was treated
`with a small amou.TJ.t of decolorizing charcoal, filtered and
`cooled. A colorless product was thereby obtained, 11.0
`gms. This was recrystallized from 80 ml. benzene, M.P.
`137-139° C. (Anschlitz therm.). Carbon, hydmgen, ni(cid:173)
`trogen, and chlorine analyses confirmed the composition,
`C16Hn02N.C7H503Cl, molecular weight 421.5.
`EXAMPLE 16
`8-quinolinyl benzoate-4-metlzyl salicylic acid salt
`10.0 gms. 8-quinolinyl bonzoate were dissolved in 100
`ml. 99% isopropyl alcohol at the boiling point. 6.1 gms.
`4-methyl salicylic acid were then added. The resultant
`solution, light amber in color, gave rise to colorless 25
`crystals ·On cooling. 9.0 gms. of pmduct were thus ob(cid:173)
`tained; this was recrystallized from 80 ml. of benzene to
`yield colorless crystals, M.P. 135.5-136.5° C. (Anschlitz
`therm.). Carbon, hydrogen, and nitrogen analyses
`checked for the composition, C16H110 2N.C8H80 3, mo- 30
`lecular weight 401.
`
`15
`
`EXAMPLE 19
`5,7 - dibromo - 8-benzoyloxyquinoline-3,5-diiodosalicylic
`acid salt
`
`(a) 5,7 - dibromo - 8 - benzoyloxyquinoline.-20.0 g.
`(0.066 mole) 5,7-dibromo-8-hydroxyquinoline was added
`to 250.0 ml. (3.1 moles) pyridine at 25° C. The clear light
`20 yellow solution was cooled down to +10° C., and 12.0 g.
`(0.85 mole) :benzoyl chloride was added at the rate of
`1 ml./12 minutes over a period of 2 hours, in the tem(cid:173)
`perature range +10 to +15° C. Agitation was con-
`tinued for 2 hours after final addition of benzoyl chloride.
`The pyridine solution was then slowly poured into 1500
`ml. of tap water, with agitation. Crystallization occurred
`and wiuhin 2-6 minutes a white solid deposited on the
`beaker wall. After 10 minutes the solid was scratched
`off from the beaker wall. Agitation was continued for
`1 hour longer. The product was filtered off with suction
`and all pyridine washed out with 1 ~ liters of tap water.
`The residue was slurried in 100 ml. accasolve to remove
`any excess benzoic acid. The solid was filtered off again,
`with suction, and washed with accasolve. The air dried
`35 yield was 21.35 g.
`The crude ester was then dissolved in 575.0 ml. of 99%
`i-propanol. The hot clear light amber solution was al(cid:173)
`lowed to cool slowly to give rise to clusters of prismatic
`40 white crystals. They were suction-filtered and washed
`i-propanol. Yield was 18.6 g.
`with additional 99%
`One gram was taken and recrystallized twice from 99%
`i-propanol for analysis: M.P.=147.0-148.0° (Anschutz
`thermometer). Analysis for carbon, hydrogen, nitrogen,
`45 and bromine agreed with the theoretical C16H90 2NBr2;
`molecular wt. was 407.060.
`(b) 3,5-diiodosalicylic acid salt.-3.0 gms. of 5,7-di(cid:173)
`bromo-8-benzoyloxyquinoline were dissolved in 30 ml. of
`benzene to give a colorless solution. To this hot solution
`50 were added 2.88 gms. 3,5-diiodosalicylic acid. An addi(cid:173)
`tional 65 ml. of benzene were required to cause complete
`solution. On slow cooling, fine colorless crystals were
`obtained in a yield of 4.0 gms. after suction filtration,
`washing with a small amount (10 ml.) of benzene; and
`55 air-drying. After recrystallization from 1benzene (1 g./
`20 ml.) the melting point was 188-189° (to a red liquid
`with softening at 187.5° C. (Anschutz therm.)). The
`product, on analysis for carbon, hydro.gen, nitrogen, bro(cid:173)
`mine, and iodine proved to be of the composition
`60 C15H902NBr2.C1H403l2, molecular weight 797.
`EXAMPLE 20
`5,7 -