US2655540A - Bis-hydrazones - Google Patents

Description

Patented Oct. 13, 1953 I 2,655,540 BIS-HYDRAZONES Heinrich Jensch, Fran Germany,

kfurt am Main Hochst, assignor to Farbwerke Hoechst Aktiengesellschaft vormals Meister Lucius und Briining, Frankfurt am Main Hochst, Germany, a company of Germany N 0 Drawing.

Application September 3, 1952,

Serial No. 307,696. In Germany July 24, 1950 6" Claims. (01. 260565) I The present invention relates to new bis-hydrazones. I have found that hitherto unknown bishydra'zones of aliphatic, vicinal dioxo compounds can be prepared, which have in one hydrazone group a guanyl radical and in the other a phenyl radical containing one of the following substituents:

The products thus obtained have the following structural formula: 7

CH: W NH NH.N=C R''.( :=N.NH.o t R i v NH:

wherein R stands for a member of the group consisting of and R stands for a member of thegroupconsisting of hydrogen, methyl, ethyl and allyl.

According to one feature of the invention the specified compounds are obtained by condensing with amino-guanidine a mono-phenyl-hydrazone of an aliphatic, vicinal dioxo-compound of which the phenyl nucleus contains one of the specified substituents. As aliphatic, vicinal di-oxo compounds there may be named, for'example, pyroracernic aldehyde, diacetyl, pentane-2.3-dione, hexene (1) -dione(i.5), pentene(1) -dione(4.5) hexane-2.3-dione, and others. u

According to a further feature of the invention the compounds may be obtained by condensing a mono-guanyl-hydrazone of an aliphatic, vicinal dioxo compound with a phenyl hydrazine which contains in the phenyl nucleus one of the three specified substituents. i l

According to a stillfurther feature of the invention it is also possible to condense with amino-guanidine a mono-'phenyl-hydrazone of an aliphatic, vicinal di-oxo compound containing in the nucleus a group which can be transformed into one of the specified substituents; and to transform this group into one of the said substituents. 1

' Suitable aliphatic hydrocarbon radicals having 1 to 3 carbonatoms, which may be used according to the present invention, are, for example methyl, ethyl, propyl, isopropyl, allyl, vinyl and others. i

The compounds thus obtained are distinguished by their eflicacy in protozoan infections, i. e. for combating babesia and trypanosomes. Moreover, the compounds possess bactericidal properties.

The following examples serve to illustrate the invention but they are not intended to limit it thereto:

,is obtained. The solution is then mixed with an excess of dilute nitric acid and the yellowmagma formed on cooling is filtered with suction and washed with dilute nitric acid. .The dinitrate thus obtained, of the compound corresponding to the formula given above, is then transformed into the carbonate by mixing it, whilev stirring,

with sodium carbonate solution. The, carbonate is filtered with suction and washed with icecold water. After having been dried at ordinary temperature it constitutes an ochre-yellow powder which, on subsequently stirring with methanol and acidifying with methanolic hydrochloric'acid,

lowing a solution of ash solution or 2.76

is transformed, with evolution of carbon dioxide, into the hydrochloride which, after cooling in ice, is filtered with suction and washed with ice-cold methanol. The product is readily soluble in water and more sparingly soluble in dilute hydrochloric acid and in methanol. When recrystallised from methanol and a small quantity of water, it does not melt up to 300 C. After hav.- ing been recrystallised from water, the dinitrate melts at 276 C. with violent decomposition. The lactate, which is obtained from the-carbonate in a manner analogous to that of obtaining the hydrochloride, melts at 253 (L-254: C., with decomposition.

The starting material, i. e. the pyroracemic aldehyde para guanyl phepyl hydrazone hydrochloride, is suitably prepared as follows: The hydrochloric acid solution of 63 grams of para-amino-benzamidine dihydrochloride (melting at 288 C. with decomposition, para-nitro-compoundby reduction with hydrogen and a nickel catalyst) which solutionhas been diamtized with 21 grams of-sodium nitrite, is mixed with an acetoacetic acid solution obtained by al- 40 grams ofacetoacetic ester to stand for 24 hours in 670 cc. of a caustic potper cent. strength and then acidifying it with 310 cc. of 2 N-hydrochloric acid. 220 cc. of saturated sodium acetate solution are gradually added to the mixture, while stirring, during which operation a thick, brownish-yellow precipitate is formed with evolution of carbon dioxide; the precipitate is :allowed to stand for several hours, filtered with suction and washed with N'hydrochloric acid .and acetone. when the product has been recrystallised from glacial acetic acid it melts at 255 C. with'decomposition. It is readily soluble in vhot water, sparingly soluble in dilute hydrochloric acid in the cold and soluble in caustic soda solution,

.forming a dark brown-yellow solution.

Example 2 an in; //NH NH.N=CH. ='N;NH.C HIN/ H:

27 grams of pyroracemic aldehyde-metaguanylephenyl-hydrazone with a small-qrmntitycof dilute nitric acid and then mixed in 200 cc. of water with a.solution of 14 grams or aminoguanidine nitra The mixture is heated for 1 hour in a water-bath, while stirring; after cooling, an excess of dilute nitric acid-is added and the (ii-nitrate corresponding to the above-formula is filtered with suotionand washed with N-nitric I acid .and acetone. It constitutes a brown-red powder which readily dissolves in hot water; it is moderately soluble in cold water, and after it has-been recrystallised from water it meltsat 262C. withdecomposition. The carbonate, obtained-therefrom as described in Example 1, constitutes a grey-yellow powder which is dried under reduced pressure and then transformed, in the same manner as the para-compound, into the di-hydrochloride. A brownish-red crystalline 'powder is obtained which, after recrystallisation from methanol and acetone, meltsat 273 C. with decomposition; it is readily soluble in-water, methanol and dilute hydrochloric acid and sparingly soluble in ethanol.

The pyroracemic aldehyde 'meta-guanyl phenyl-hydrazone is prepared in a manner analand obtained from the.

nitrate are acidified solves in water ogous to that of the para-compound, using metaamino-benzamidine dihydrochloride (see "Berichte der Deutschen Chemischen Gesellschaft, vol. 28, page 486); it is precipitated as the nitrate by mixing the solution 0! its hydrochloride with dilute nitric acid. The nitrate constitutes a light red to brown powder which, recrystallised trom water, melts at 209 C.-210 C. with decomposition.

Erample 3 on. OH: /NH ,NH.N=t:-- =N.NH.C/ EN NH) I HrN "25.5 grams of diacetyl-mono-para-guanylphenyl-hydrazone hydrochloride in cc. of water are mixed with a hot solution of 14 grams of aminoguanidine nitrate in 65 ,cc. of water. whereupon the mixture is heated in a water-bath. while stirring, until dissolutionhas taken place. On coolin a practically colorless magma is formed which is stirred with an excess of sodium carbonate solution, during which operation it is transformed into the voluminous carbonate which is centrifuged and washed several times with water. After drying, the carbonate is mixed with methanol, while stirring; by acidifying the mixture with methanolic hydrochloric acid, it is transformed into the dihydrochloride which is filtered with suction and washed with acetone. It constitutes a yellowish powder which readily dissolves in water, forming a. reddish-yellow solution. By means of dilute caustic soda solution the practically colorless crystalline base of "the above constitution is precipitated from the solution. After recrystallisation from acqueous methanol, the base melts at 240 C. with decomposition.

The starting material can be obtained according to the method described in Example 1. in the form of the hydrochloride, by coupling diazotized para-amino-benzamidine with methylaceto-acetic acid. The hydrochloride constitutes a feebly reddish powder which is sparingly soluble in cold water and readily soluble in hot water. When recrystallised from water, it melts at 272 'C. with decomposition; the base precipitated with dilute caustic soda solution melts at 199 C.- 200 C. with decomposition.

24.6 grams of diacetyl-mono-meta-gulm lphenyl-hydrazone hydrochloride are heated in the water-bath together with 50 cc. of water and a solution of 15 grams of amino-guanidine carbonate in about -'70 cc. of 2 N-hydrochloric acid until complete dissolution has taken place. After cooling. the solution is mixed with concentrated hydrochloric acid and the salt which has separated is filtered with suction in'the icecold conditi and washed with ice-cold dilute hydrochloric acid and acetone. The .di-hydrochloride of the above base constitutes an almost colorless incompact powder which readily dison heating-and forms a yellow solution. when recrystallised from methanol andacetona it melts at 302 C. with decomposition.

decomposition.

Example 5 CzHs CH3 NH 1 NH.N=0 o=N.NH.o

NH2 0 HzN 20.5 grams of pentane 2.3 dione-3-paraguanyl phenylhydrazone hydrochloride are weakly acidified and then heated on the waterbath, while stirring, together with 100 cc. of water and a solution of 9.8 grams of aminoguanidine nitrate in 45 cc. of water, until a clear solution is formed. After cooling in ice, the fine crystalline precipitate is filtered with suction and stirred with an excess of sodium carbonate solution. The carbonate is formed during this operation in the form of a precipitate of the nature of a thick oil which, on cooling and rubbing, becomes crystalline. After drying, the carbonate in methanol is acidified with methanolic hydrochloric acid, during which operation a pale yellow magma of the dihydrochloride of the compound having the formula given above, is formed. The compound dissolves in water and forms a red-yellow solution; when recrystallised from a large quantity of methanol, it melts at 244 C. with decomposition.

The starting material is obtained as described in Example 3, using ethyl-acetoacetic acid. It constitutes a reddish crystalline powder which dissolves in hot water and forms a red-yellow solution. The base is precipitated by means of dilute caustic soda solution. When the base has been recrystallised from water and a small quantity of methanol, it constitutes a colorless, fine crystalline powder which, on dryingon the water-bath, assumes a brown color. It melts at 113 C.-114 C. with decomposition.

grams of hexene-(l)-dione-(4.5)-4-paraguanylphenyl-hydrazone hydrochloride in 130 cc. of water are weakly acidified with dilute hydrochloric acid and then heated on the waterbath for about hour with a solution of 9.3 grams of amino-guanidine nitrate in cc. of water. After cooling, the carbonate is precipitated with potassium carbonate solution. After having been washed with water, it constitutes a light yellow powder which is covered by pouring methanol upon it and, on acidifying with meth anolic hydrochloric acid, it is transformed, with evolution of carbon dioxide, into the yellow dihydrochloride of the base named above. When recrystallised from methanol and acetone, it melts at 230 C. with decomposition.

The starting material is obtained in a manner analogous to that described in Example 3 by using, instead of methyl, the allyl-acetoacetic acid which is formed in a manner analogous to the process described in Example 1, by shaking the ester for several days with caustic potash solution. A feebly reddish, fine crystalline powder is formed. The base may be precipitated from the aqueous solution by means of dilute caustic soda solution. After recrystallisation from water and a small quantity of meth anol, the base is substantially colorless; on drying it assumes a brownish-yellow coloration; it melts unsharply at about C. Bymeans of sodium carbonate a carbonate is precipitated which crystallises from water in the form of small brown needles melting at 66-67 C.

38 grams of pyroracemic aldehyde-paraguanidinophenylhydrazone hydrochloride in'100 cc. of water are heated on the water-bath together with a solution of 25 grams of aminoguanidine carbonate in about cc. of 2 N-hydrochloric acid. After the addition of hydrochloric acid in excess and cooling in ice, the dihydrochloride of the above compound is filtered with suction and Washed with'2 N-hydrochloric acid and acetone. It is purified by dissolving it in water, filtering the solution and reprecipitating with hydrochloric acid in excess. A substantially colorless powder is obtained after recrystallisation from methanol and a small quantity of water with subsequent addition of acetone. The powder melts at 275 C.276 C. with decomposition. i

The starting material is obtained 'by the process described in Example 1, using para-aminophenyl-guanidine instead of para-amino-benzamidine. A weak reddish, crystalline powder is formed which, after recrystallisation from water, melts at 278 C. with decomposition. Paraamino-phenyl-guanidine may be obtained in the form of the carbonate when recrystallised from water, melting at 180-181 C. with decomposition) by precipitating with saturated potash solution in excess either the catalytically reduced nitro-compound or the para-acetamino-phenylguanidine (obtained from para-amino-acetanilide and cyanamide, the carbonate when recrystallised from water melting at 220 C. with decomposition) saponified with dilute hydrochloric acid.

Example8 14 grams of pyroracemic aldehyde-para-(guanyl hydrazone ormyl) -phenyl-hydrazone hydrochloride are heated on the water-bath together with 70 cc. of water and a solution of 7.5 grams of aminoguanidine carbonate in about 35 cc. of 2 N-hydrochloric acid until dissolution is complete, whereupon the solution is mixed with hydrochloric acid in excess and the dihydrochloride of the compound of the formula given above is well cooled, filtered with suction and washed with ice-cold dilute hydrochloric acid and acetone. It constitutes a red-brown powder which readily dissolves in water and forms a red solution. The powder is recrystallised from methanol and acetone; it then constitutes a brown crystalline powder melting at 266 C. with decomposition. The nitrate whem recrystallised from water melts at 250": -251 C. with decomposition The starting. material mayvbe prepared in the manner described=in-Example 1 from paraamino benzalguanyl-hydrazene andacetoacetic acid; and when resrystallised from waterit iconstitutes -a brown-red'powdermelting.;,at 120 C with. decomposition.- The para-'ammo-benzalguanyl-hydrazone maynbe obtained as-carbonate in the form of a yellow powder by precipitating with potassium carbonate solution para-acetamino-benzalguanyl hydrazone (when recrystallized from water, melting-at-238 C. with decomposition) which has been saponifled with dilute hydrochloric acid. The powder thus obtained melts at 235 C. with decomposition.

18 grams ofpyroracemic aldehyde-meta-(gua nyl hydrazone formyl) -phenyl-hydrazone' by drochloride' are heated on the water-bath, while sth'ring -together with 8O cc.-- of water and a foobly acid solution of 10 grams of amino-guanidine carbonate in-about 50 cc. of 2 N-hydrochloric acid; A -dark-redsolution .is obtained within about /1 hour. On additionof hydrochloric acid in excesspa light-brown magma of the dihydrm chloride -of'the above'base is formed which is cooled in ice, filtered with suction and washed withdilute hydrochloric acid and acetone. A reddish-grey powder is obtained'which on dissolving -in water forms a red solution. It may he arecrystallisedifrom alcohol and acetone and melts. at 149-C.-150 C. with slow decomposition accompanied byswelling:

The starting .material =may be prepared as described inExample 8, using meta-aminobenzalguanyl-hydrazone (obtained from the nitrocompound by catalytic-reduction; the dihydro chloride -melts at"2'75 C.. with decomposition). When recrystallised from water,it constitutes a teebly brownish powder which 'assumesa blackviolet. coloration by the addition of concentrated hydrochloric acid; The powder melts-at 222: C.

withrdecompositiomi.

Example 10 ([JH: OH; NH NH.N=c- :=N.NH.c

NH: 0 HiN A diazonium hydrochloride solution of paraarnino benzamidine is reduced at a temperature between -10 'C'. and 5 C. with a strong stanno'uschloride solution inhydrochloric acid, the reduction product is neutralised with caustic soda solution, the solution is detinned and evaporated to-dryness under reducedpressurefithe residue is extracted with alcohol and the alcoholic ex tractis mixed with'ether. The dihydroc'hloride of; the'para hydrazine-benzamidine .is thus :obtained which is recrystallised from alcohol and then melts at 211 C.2l2 C. with decomposition. A solution of- 3 grams of this salt 'ismixed with a hot aqueous solution'of. 1.75 grams of diacetylmonoguanyl-hydrazone and-the-mixture' is acidifled-awith dilute hydrochloric acid; After some time dilute'hydrochloric acid is added in excess,

after cooling in ice the-precipitate is-filtered with suctionand. washed withice-cold dilute hydrochloric'acid and acetone. The pale yellowpowder is soluble in water. andforms a yellow solution. The nearly colorless base, the* diacetyl- (guanyl) (para-guanyl-phenyl) bis hydrazone, is precipitated from the solution by means of dilute caustic soda solution. The-base melts at 240-241 C; with decomposition-L The mixture with the base of Example 3 has the same'm'elting point.

The diacetyl monoguanyl hyd'razon'e (when recrystallisedfrom water, melting at 214 C. with violent decomposition) may'be 'obtainedbyf 'ca'refill reaction 'of (11061; 1 with the hydrochloride of "amino-guanidine.

Example-.11

Pyror acemic aldehyde-para-tormyl-phenyl-hy drazon'e may be obtained 1 by-- coupling diaz'oti'rled paraami'no-benzaldehyde with acetoac'etic' acid. Wheni'ecrystallised from benzene, the compound constitutes-a feebly reddish po'Wdrmelting'ht 152- 3 grams of the hydrazonethusobtained are dissolved in l methanol, the solution is mixed with a hot aqueous solution -of "45'gr'ams=ot amino-guanidine nitrate fand, after the "addition of asmall quantityot dilute nitric acidi'the mix ture is -hea'tedfor a prolonged'tinieon' the waterbath. After the additionof dilute'nitric acid in excess, the dinltr'ate of the ua'hyl-hydrdzohopyroracemic aldehyde (para=guanyl-hydrazono formyl) -phenyl-hydrazone is filtered with suction and washed-withwateri when recrystallised front-water, the product melts at 250 01-251- C. with decomposition.- The mixtur'e"wit-h the 'dinitrate ot EiiampleB has'the same melting point.

Example 12 v CH3 NH'.N=cH. =N.Nn.o

(LEN

HrN

10.15 grams of pyroracemic aldehyde-metaguanidino-phenylhydrazone-nitrate are heated for 1 hour in a water-bath together witha solution of :5 grams ofaminog-uanidine-nitrate in 005 of-water'having 'been'aoidifled with dilute-hy drochloric acidx The-solution produced-separates on cooling the dinitrate-oi the above-named base which is filtered -with suction-and then washed first with water and then with acetone. It may -.be* recrystallized from aqueous methanol, with a subsequent addition ofacetone, and'then forms'- a--fine, crystal-line, reddish-gray powder which'sparingly dissclves in cold water,- but readily-' dissolves in hot water. The product melts at 284 0., .withdeoomposition; The base dissolves in sodium hydroxide solution used in excess.

The starting-;material may 'beprepared as follows 12 grams of meta-acetaminophenylguanidine-carbonateiobtained from the hydrochloride -0f=meta-amino -acetanilideand cyanamide byprecipitation -with'potassium carbonate solution;afterthe recrystallization from water, the-nitrate-melts "at 205 C., with decomposition) are-heated for- 1 hourin awater-bath together With- BO -cc.--ofwater and'20- cc. of concentrated hydrochloricacid. Thehydrochloride ofmetaaminop'henyl-guanidine which is formed during this heating operation is diazotized with 3.5 grams of sodium nitrite and the diazonium solution is mixed with an acetoacetic acid solution obtained by saponification of 7.5 grams of acetoacetic ester with 3.5 grams of caustic potash in 125 cc. of Water and a subsequent acidification with 60 cc. of Z-n-hydrochloric acid. After the addition of saturated sodium acetate solution to the mixture until a reaction to mineral acid can no longer be detected, a red coloration sets in with evolution of carbon dioxide and, after the addition of dilute nitric acid in excess, the pyroracemic aldehyde-meta-guanidino -phenyl-hydrazone nitrate separates and is filtered with suction and then washed with very dilute nitric acid and acetone. After the recrystallisation from methanol and acetone, the product melts at 218 C. with decom position. It constitutes a feebly reddish, crystalline powder.

Example 13 EN OH; OH; NH

\ &

C.HN NH.N=O- =N.NH.C HEN NH:

'7 grams of diacetyl-para-guanidino-phenylhydrazone-hydrochloride are heated, while stirring, for 1-2 hours in a water-bath together with 3.6 grams of aminoguanidine-nitrate in about 150 cc. of water, after the addition of a small quantity of dilute hydrochloric acid. Dilute nitric acid in excess is then added and after cool ing the product is filtered with suction and washed with very dilute nitric acid and with acetone. The dinitrate of the above base is thus obtained in the form of a pale yellow powder which rather readily dissolves in hot Water to form a yellow solution, but which is hardly soluble in cold water. On stirring with hot sodium hydroxide solution, the base is formed which, when recrystallized, still in the moist state, from methanol, constitutes, after drying, a goldenyellow powder. The product melts at 180 C. with decomposition. It is readily soluble in dilute acetic acid; with dilute hydrochloric acid in excess it forms the crystalline, colorless di-hydrochloride.

The starting material is obtained by the addition of saturated sodium acetate solution to the mixture of a diazonium hydrochloride solution of para-aminophenylguanidine with a methyl-acetoacetic acid solution in the form of a solid, colorless hydrochloride. When recrystallized from aqueous methanol with the subsequent addition of acetone, the product melts at 300 C. with decomposition.

Example 14 011, OH: NH

NH.N. =N.NH.C

16 grams of di-acetyl-meta-(guanylhydrazoneformyl) -phenylhydrazone-hydrochloride and 7.5 grams of aminoguanidine-nitrate are heated in the water-bath in '75 cc. of water which has been acidified with dilute hydrochloric acid, during which operation a very dark-red solution is gradually formed. While the solution is still hot, it is mixed with dilute nitric acid in excess.

After cooling, the dinitrate of the above-named base which has separated is filtered with suction and washed with n/ l-nitric acid and acetone. It constitutes a reddish-gray powder which readily dissolves in hot water to form a red solution. When cooled, the solution assumes a jellylike consistency. On heating with dilute sodium hydroxide solution, the base is formed. After recrystallization from methanol and water, a feebly reddish powder is obtained which melts at 238 C. with decomposition. The powder readily dissolves in dilute acetic acid to form a reddish solution; a jelly-like hydrochloride is precipitated from the solution by means of hydrochloric acid applied in excess.

The starting material is obtained in the form of the hydrochloride, as it is described in Example 9, while using methyl-acetaoacetic acid as a feebly reddish powder, which, when recrystallized from methanol and ether, melts at 242 C. to 243 C. with decomposition.

This application is a continuation-in-part of application Serial No. 237,061 filed July 16, 1951.

I claim:

1. The compounds of the following general formula C.HN

wherein R stands for a member selected from the group consisting of hydrogen and aliphatic hydrocarbon radicals containing 1 to 3 carbon atoms.

2. The compounds of the general formula (EH3 /NH RN NH.N=CH.C=N.NH.C/

0.1m NH, HaN

3. The compounds of the general formula CH3 CH3 NE g NH.N=C--C=N.NH.O

/CHN EN 4. The compound of the formula OH: NH l NH.N=CH. =N.NH.O N. oJIN HIN 5. The compound of the formula HN CH3 NH l /C.HN NH.N=CH.C=N.NH.C HzN NH,

6. The compound of the formula HN on; OH: NH 6 1 (LEN NH.N= o=N.NH.c HzN H:

HEINRICH J ENSCH.

No references cited.

Claims (1)

1. THE COMPOUND OF THE FOLLOWING GENERAL FORMULA