[1]Patented May 15, 1923. 19455,495 UNITED STATES PATENT OFFICE.. AUGUST KLAGES, OF XAGDEBURG-.qftQST, GERXANY, ASSIGNOR, By XESNE ASSIGNMENTS, TO THE, CHEXICAL FOUNDATION INC. A CORPORATION OF ]DELAWARE. XERCURY 3)ERIVATIVES OF AROXATIC COXFOUNI)S AND PROCESS OF, XANUF'ACTU RING SAXE. No 3)rawing. Application filed February 4,1915, Serial No. (;,052. Renewed D e c e m b e r 9 , 1 9 1 9 . S e r i a l N o . 3 4 3 , i g 4 l . To azlwhom it may coneem: Be it known that I, AUGUSL.@ KLAGES, a subject of the Germ.an Emperor, and resident of. Ma-deburg-Siidost, in the Kingdom r) of Prussia, German Empire (a4d whose po-st-office address is c/o SacchariiiFabrik Aktiengesellschaft, vorm. Fahlberg, List & Co., same place), h@-ve invented new and :Useful Improvements in Mercury Deriva10: tives of Aromatic Compounds an(I Processes .of Manufacturing Same, of w@ich the following is a full, clear, and exact specification. This invention relates to mercury deriva15 tives of 9,romatic compo'unds having the g@neral formula X--C 0 \R/ 20 iri which X represents one of therradicals or < 25 wb.ile R represents a-phenyl group in which one or more of the hydrogen atoms may be replaced by halogen and to a process of maniifactu'ring said mercury derivatives. 30 These products can on-one hand be used as colouring, matters, on the other hand they are suitable for medicinal purposes in view of the mercury contained therein, especially for use as antilueties. A process for the production of fluorescein 35 salts containing mercury is already known. According to this process fluoresceins which belon to the class of compounds above re@he presence of alkalis and the correspond40 ing alkali salts are obtained by evaporating the solution. If it is tried to sei?arate the free fluorescein mercury derivatives from t@e. oducts obtained in this process by prePr cipitating them with hydrochloric a@id in 4@ the cold it is excessively diflieult io filt@r off the precipitates an(f in view of their colloidal condition it is very difficult to free them f rom adhering or absorbed mercury 50 salts. When precipitating with hydrochIGr-ic acid while l@eating products are obtained which contain mercutic chlorid, as a, portion of the mercury is split off from the complex. The complex mercury compounds are also unstable, in godium caibonate solution and they slowly split off mercury in the 55 form of a grey precipitate even at ordinary tempera ture. 'Further the complex mercury compounds obtained by - this known process are not pure, but contain other producis in which the mercur.y is less firmly 60 bound and which therefoi@ yield precipitates with ammonium sulfid solution even in the cold. It is true that by extracting the products with alcohol or acetone it is possible to remove 'the adhering mereury 65 and the excess of fluorescein, however, the products when aip]?Iied to animals silow irregular ities Gf action and it must be c'oncluded therefrom that they are not homogeneous and pure. Probably they contain, TO besides the complex mercury deriiatives, so called semi-complex derivatives which are formed as intermediate' products @ and in which @the mercury is introduced intg the'@' @HT-co-o-, hydroxyl-group, s@ch products bein@ very 75 pGiso4ous beca;use of their instability While these disadvantages are not v6ry material if the products are used as colour@ng matters, it is evi.dent that they make it impossible to use,the compounds !or medic- 80 inal purposes. According to this '-invention all these drawbacks are av6ided. It has been found that by preparing a mercur y derivative in all abs6lutely -n6ut,ral,85 solution it is possible to obtain homo'geneous pure products in a form allowing of easy separation. This is accomplished by heating the arom eins, sacchareins or suceineins) with a large excess of a mer@uric salt, especially mercuric chlorid. If some mercuric oxide is separated it is re-dissolved in the excess of mercuric salt solution and can be removed 95 by merely washing with water without any addition of acid. Products containing two atorns of mercury are thus obtained in the form of fine granular precipitates, which can be easily and rapidly filtered off. B 100 repeated wa'shing wit-h h6t water the pro7- ucts are freed, from mercuric chlorid and they. are very stable with respect to am-- moniums sulild even under the influence of ferrey to are treated with mercuric salts in , utic compoi@nd above referred to (phthal- 90
[2]1,455,495 heat. For iomoviing adheriiig fluorese,ein grams) prepared aceording to Fischer, Anor o,th@r simil@r staruing material the prod- nalen der Chemie, volume 183, page 63 (see ucts are extract@d with alcohol or acetone. also Meyer, Berichte der Deutsc&n ChemisThe n6w process has the further advantage clien Gesellsehaft, volume 28, pago- 2959) by 5 that it renders possible the manufacture of - heating three pa;rts by 'weigh-t of phthalic 70, anhydiid-e 5 part@ of resorein and 5 parts of concentrated sulfuric acid to from, 140 to 1500 are dissolved in 5 the theo retic al.'q uantity of caustic soda (80 cubic centim6ters of -normal caustic goda, the hot solution ig then 75 slowly poured into a boili ), solution of 110 gra,ms of mercury chlorid . '@,15 times the, theoretical quantity) i '400 cubic centimeters of n water qnd boiling continued for 20 minutes. The mercury, comp-ound segarates iniinedi 80 in ately and is filtered as Example l@,well washed, again suspended in I litte of hot water, heated to boiling, filtored, tho ughly ro washed until no m'ercuric 'chloride can be detected in the :ffltra-te,, well pressed, and 85 dried at a gentle -heat. The yield is 30 grams. The precipitate is then extracted with alcohol duting two liours. The mercury derivative is a clear brown p-owd6t'of a color somewhat darker than that 9( of the product containing no m(- ,reury. It is soluble in sodium carbonate aiid alkali S@0lution wit-h a red colour;: on dilution iL stron 9 fluorescence i@ prodiieed. The solution in ammoiaia liquor is not so intensely colouted 95 and the fluorescence is stroiwger. , In the ammolaiacal spl -4tion ammonium sulfid causes a separation of mercury only on heating. I The'product is sparin@,71@ s6luble or insoluble 'Ln the usual organic solvents. 100 On silk intensely yellbw -,shades are -obtained. 3. Dibromll7luoreseeindeiioative.-@@Dibromfluorescein is obtained by adding the theoretical quantity. of bromille to -an alcoholie, 105 solution.of fluorescein cooled with ice. The rnelting point of the dibromfluorescein is' 261-262'. 19.6- grams of dibromfluoresceiii (4/100 gram moleciile) are dissolved ii@. 80 cubic 110 centimeters of normal caustic soda and'100 cubic centimeters of water. The h6t solu.@ tion is then added to a boiling solution of 80 grams of m6reuric chloride in I litre of water and boiled for several minutes. A 115 clear red pre6ipitat@ is immediately formed which - recipitate easi,ly geparates and can p rea-dily be filtered iind washed. If th,6 washalcohol and acetone during 4-i hours. T%e product forms a brilliant red powder' soluble - with ,t red coloration in sodium ca.rbonate or -caustic alkali solutions, on 125 dilution as well as in ammoniacal solution a green fluorescence is olitained. On addition of ammonium sulfid solution 'to the ammoniacal solution mercuric sulfid is precipitated only on lieating. The. product is 130 by h@drochloric acid in the form of a yellow-, water no longer contains me'reury , chloride 55 ish precipitate the colour of which is again the precipitat@ is- dried. The yield is 26 120 cha @ ed ipto reddish-yellow by washing with' &,ams. The product is then extracted with deiivatives which cannot be prepared by the known process. 'Indeed, while mercury can be introduced into fluoresc eins and their chlorine derivati'ves adeordi,ng to the kn-own 10 process above relerred to this does not apply. to brotine and iodine derivatives. For instances in ihe case of tetrabromfllioreseeiii the i' n or at least e-arlynoreactioiieven re s 0 n if - it is boiled several, hours with mercuric 15 ebl6rid and sodium carbonate solution. On the contrary according to the present process mercury can be very oasily introduced evon into these products. 20 Examples. 1. F@uoreseein d@7,ivative,16.6 grams -of fluoreseeiia (1/20 gram molecule) ard dissolved in 200 cubic centimeters of w'ater with '25 6.3 grams of dtied @sodium carbonate (1/20 - gram,molecule) while boiling. ' The solution is then slowly poured into a boiling solution of 81 grams of mercuric chloride (3/10 @ram molecule) in I litre of water'and boiled dur@30 ing one, hour. An orange prec.ipitate is immediately formed and then filtered while hot. The precipitate may be readily filtered and washed., After pressing the.@recipitate is again suspeiaded in I liire of water, heated 35 W boiling, again filtered and washed until ihe wash water does not show any tuibidity or ditrk coloration on addition of bbmmonium sulfid solutibn. , The precipitate is then dried at,aboiit 80'. @The yield is_abopt 40 grams 40 and is approximately quantitative. For removing the last traces of mercuric chloride, the product is ext@acted with acetone during 2 hours uintil the solvent drips, off without any coloration and is then further extracted 45 during 2-21 hours with ethyl alcohol. The product is insoluble or sparingly solubl-e in benzin, a,cetone, @ther, chl-oroform, acetic ether, glacial acetic acid and benzene. Sodium carbonate solution, caustic soda r)O and ammonia solution dissolve it with 'a dark red colour, thd diluted solution showing a strong yellowish green flixo@eseence. From these solutions the compound is precipitated 119 hot water'. On addition of -animonium sulfid solution to a soluti6n of the compound in ammonia sdl-Lition no pr@cipitate is@formed 60 while cold, only on heatina a bl,.tek coloration is obtained. The coinpound ptoduces intensely yellow shades on silk and mordanted cotton. 2. Methylfluoreseein. de7ivative.-41100 65 gram moleciile of resoreinphthalein (14.4
[3]19455,495 nearly insoluble in' ihe usual orenic solvents, except glacial[ acetic 'acid, in which the compounct is appreciably soluble. On silk rose shades are obtained. 4. 7'etrabromfluorescein derivative.@19.4 grams of eosin (3/100 gram molecule) are dissolved in 60 cubic centimeters of normal caustic potash and slowly dropped into a boiling solution of 81 grams of mercuric 10 chl'oride in 200 cubic centimeters of water. Boiling is continued for 45 minutes. The product is then filtered, thoroughly washecl and dried. -The yield. is 23 grams. The product is then extracted during 2 hours 15 W'Ith alcohol a-hd then during 2 hours with acetone. The product forming a red powder some- what darker than eosin is soluble with a red coloration in sodium carbonate and caustic 20 alkali solutions, on dilution the solutions show a weak fluorescence. By addition of hydrochloric acid a more distinctly coloured product is precipitated. By addition of ammonium sulfid solution the product is 25 more easily decomposed than the corre,spondiilg fluorescein derivative containing no btomine. T@e product is sparingly soluble or insoluble in the usual organic solvents except 30 gl acial acetic acid in which it is. appreciably soluble. 5. Tetraiodfluoreseein derivative.-18 grams of commercial erythrosin'(2/100g@am molecule of tetraiodfluoreseein -- potassium 35 salt) are dissolved in 125 cubic centimeters of water and slowly poured into a boiling solution of 64 grams of mercury-chlorid in 200 cubic centimeters of water. Boiling is then continued for 15 minutes. The red 40 precipitate obtained can easily,be filtered. For removing adhering mercuric chloride it is, after pressing, again suspen(1'6d in I to litres of water and then lieated to boiling. It is then filtered, washed and driea. the precipitate . is at first iriearly white and then turns to a clear, brown with a -violet shade. The precipitate is, boiled during 15. minutes, then filtered and thorougbly washed until the filtrate is free from mercuric 70 chloride.. The weight of the dry product is 32 grams. After@two hourg, ejktraction with-@, acetone a powder is@ obtain-ed having a Weakly rose-violet coloration. In c:iustic alkali and ammonia solutions 7.5 the - product is soluble with it darli: violet coloratio n. It is some@vhat soluble in @thyl and methyl alcohol,'acetone and ethor, very ea@ily, soluble in glacial, a'cetic acid ftom which it c-an he separated in the form of 80 white flakes. Ammonium sulfid solution causes a separation of iiiercuric sulfid'only on boiliiag. On silk violet shades are obtained. On washing with diluted hydrochloric acid this 85 colorati6 n is removed, while- it is reproduced by treatment with sodium carb6nate solution. 7. Tetraiodphenolphthalein derivative.-, 6.4 grams of tetraiodphenolphthal6in go (2/100 gram m6lecule) are- dissolved ill 44 grams of sodium carbonate and 400 cubic centimeters of water and added to a, boiling solution of 40 grams 6f mercury chlorid. Boiling is then continued during I hour. 95 A brown precipitate is obtained *hfcli is filtered, thoroughly washed and dried. The.. yield is 14 grams. The brown,p owder is soluble in cailstic alkali solution with a blue coloration hav- 100 ing a viblet shade. It is insoluble in alcobol, ether and acetone, appreciably sciluble in glaci-,tl acetic :icid. It is stable against - .tmmonium sulfid solution@in the cold. The product produces clear blue shades on' silk. 105 8. HydroquinonephthaMin derivativ@.@ ephthaiein is obtained by heat-.@ s of . phthalic anhydride ' 55 roquinone aiid 200 grams of 45 The yield is 12.5 grams. The Rro.duct is stann c cholrid durin@ 15 'hours (see Be-- 110 then extracted with ale6hol du.ring some richte der Deutschen Chemischen Gesell-' hours. s@haf t, volume 11, page 713, volume 28, pagpThe mercury derivative f@rms a red pow- 2959, Beilstein, Handbuch der or anischen der of the same coloration as the startirig Chemie, third edition, volume II, page 50 material. 'It is solul>le in caustic alkal-i solu- 2065). 115. tions with a dark 'red coloration. On dilu- 19.8 grams of hydroquinonephthalein tion and on solution in ammonia fluores- (6/100- gram molecule) are dissolved in 120 cence is produced. On boiling with am- cubic centimeters of @normal caustic soda monium sulfid solution a biaek coloration is and 180 cubic centimeters of,water. The 55 slowly produced. solution is added.to a boiling solution of 120 The product is' sparingly soluble or in- 150 grams of mercury chlorid in 500 cubic soluble in the usual organic solvents. By centimeters of water and b oiling c@ontinued means c)f glacial acetic acid ii is rather easily for 10 to 20 minutes. The main quantity of dissolved. On silk rose shades are obtained. the mercury compound is precipitated in 60 6. Phenolphtha:Wn derivative.' 19 irams the form of a- brown powder, while a ce'r- 125 of phenolphtbalein (6/100 gram molecule) tain quantity is separated @ in the form of a are dissolved with 12.8 grams of sodium car- viscous mass which ho ever is probably bonate and 300 cubic @entimeters of water chemically identical with the brown powand poured into a ooilin,-, solution of 108 der. . The prodtict is filtered, thoroughly 65 grams of mercury chlorid. The colour of washed and dried. The *Id is 36 grams. 130
[4]9. Oxyhydroquinonephthalein derivative.-14.6 grams of oxyhvdroquinonephthalein (4/10 gram molec@le) (Beirichte der Deutschen Chemiselien Gesellsehaft, volume 34, pages 2299, 2617, 2637) @Lre dissolved in 80 cubic centimeters of normal caustic pot@ish and added to a boilin solution of 100 9 grams of mercuric chloride. Boiling is continuectl during 10 minutes. The produced 10 black precipitate is filtered off and th6roughly @vashed. The yield is 33 grams. The substance.is soluble in caustic alkali solutions with a reddish-violet coloration. On addition of ammonium sulfid, solution 15 niercury in the form of sulfid.separates 6nly on boiling. On silk the compound produces teddish-violet shades -@vliieh are rem6ved by treatment with hydrochloric acid and reproduced by addition of ..sodium carbonate. 20 10. Resoraimuceigiei?z, derivative..- 17 grams of, resoreinsuceincin (6/100 gram molecule) obtained by heating one gram molecule of suceinic acid anhydride with 2 gkam molecules of resorein in the zi presence 25 of ne chlorid during 6 liours, are dissolved in 120 cubic centimeters of normal caustic so(la by heat.ing and slowly added to a bo,,_ ingd, scilutioii of 200 grams of mercuric chloride. Boiling is continaed for 15 min30 utes and the dark rusty brown pre6ipitate which is immediately formed, is.filtered and tiloroughly washed. It is then well pressed, again suspended in water, heated to boiling, filtered, washed and dried. The yield is 45 35 grams. The product is easily soluble in sodium efrbonate, caustic. alkdli and ammonia soluti.on with a reddish-brown coloration and green fluorescence. The ammoniacal solu40 tion yield's on addition of ammonium sulfid a black precipitate only on continued heating or boiling. On silk rose sh@des are obtained. 11. Cresorein@uceinein derivative.-Cre45 SorcinsucciAein is obtained by heatin molecular . proportion of suceinic anhydrgide with 2 mole'eular proportions of cresorcin in th-e presence of zinc chlorid to 160" to 2050 C. 50 22 grams of cresoreinsuceinein '(7/100 gram molecule) are dissolved iii a slight excess of diluted 'Caustic soda (correspond@-ng to about 160 cubic centimeters of normal caustic'soda) and slowly poured iiito a 55 boiling concentmted soltition of about 200 grams of mercury chlorid.. Boiling is continued for 15 miiautes. The brown precipita,te is flltered, washed, suspended in water, a 'n heated to boiling, filtered, thoroughly ag I 00 washed, pressed and dried. The yield is 50 grams The brown compound is s-oluble in sodium carbonate and.caustic alkali solutiori with a reddish bro@Vn coloration.' On boiling with 05 amynonium; sulfid solution a -black. coloration is obtained On silk saln@on red shades are obtained. -12., Resoreinsaccharein cler@vative.-Resoreinsaccharein is prepared a@,cording to the specification of German Pgtent No. 70 100,779. i8.35 grams of resoreinsaccharein (5/100 gram molecule) are dissolved in 100 cubic eentimeters of normal caustic soda and poured wliile hot into a boiling.con'centrated 75 solution of 150 grams of mercury chlorid. After 15 minutos' boiling the brown. precipitate is Iltered off thoroughly washed and dried. The yield i's 35 grams. The product i then extracted with.'alcohol. The brown 80 powder -is sparingly sotuble in sodium carbonate and ammonia solution,,more easily soluble in caustic alkali. It is insoluble in ligroin, alcohol, acetone and benzene' and is decomposed by ammonium sulfid solution only on heating. What I
