Патент USA US2408098код для вставки
Patented Sept. 24, 1946 _ 2,408,096 UNITED STATES PATENT‘I'QFFICE POLYHYDROXYAIHINO COMPOUNDS John ‘S. Pierce, Richmond,‘ Va., and John H. Wotiz, Pittsburgh, Pa.; said Wotiz, assignor to said Pierce No Drawing.v Application May 1, 1944, Serial'No. 533,644 5 Claims. (01. 2sd-5s4.) 2 The present invention relates to new chemical compounds and to their'methods of manufacture. following examples. It is understood that these . one object of-this invention is to provide a. the invention in any way. examples are illustrative only and do not limit , means of holding bismuth in neutral solution, in high concentration. This is extremely important . from a therapeutic standpoint. I ' > , panol dihydrochlorz‘de Another object of this invention is to provide a means of holding iron salts in solution, par ticularly ferric salts in alkaline solution. Another object is to hold in solution'a‘high concentration of various metallic salts with a low concentration of the cation of the salt. Such a - (HOCHQSCNHCHZCHOHCHZNHC(CHBOHMBHCI amino-methaneiloi moles) and 92.5 grams of epichlorohydrin‘ (1.0' mole) and 200 ml. of 95% alcohol'was heated on a boiling water bath under reiiux' for '5 hours. The reaction mixture thus formedvwas treated with 100 ml. of concentrated hydrochloric acidjwith stirring. A heavy pre cipitate was" formed. The mixture was cooled and ?ltered withgsuction'. ‘The precipitate was ceutical applications as is shown in the discussion our invention. .. > ' 4' ' -' Y " v ‘ A mixture of 242 grams of tris(hydroxymethyl) - property has important industrial and pharma of " 'ExAMPnE '1‘ 1,3-ln's [iris (hydroazymethyl) methylamino] -2-pro- ' , Another object is to furnish intermediates for the dye industry, for detergents and for pharma recrystallized from an alcohol-water solution. In general, our invention relates to polyhydroxy There was obtained 190 grams (51% of theory) of compounds containing two amino groups and four s29 1‘,3-'bi's [tris(hydroxymethyl) methylamino] -2-pro ceuticals. ‘ . or more hydroxyl groups and to means of pro panol dihydrochloride, ‘melting at 185-1879. On further puri?cation, the product'melted at 186 188} Calculated for CiiHzaovClzNzt Cl, 19.13%‘. ducing these compounds. More speci?cally, it relates to polyhydroxy amino alcohols made up of two groups, one containing an aminov group Found, and three hydroxyl groups and the other contain ' ing one or more hydroxyls, these groups ‘being atoms.~ , . ‘ ' ‘ " ' ‘ ' EXAMPLE ‘ 2 ' ‘ ' ’ 1,3-bz's [trz‘s (hydroxymethyl) methylaminol ~2-pro panel dihydrochloride connected by linkage of amino nitrogens through carbon 19.07%. ' ‘ One phase of this invention in which wjev are particularly interested is the class of compounds , l l (HOCHQgCNHCHgCHOHCHgNHC(CH2OH)a.2HC1 Glyceroldichlorohydrin was heated with‘ two containing two tris(hydroxymethyl) ,methylamino molar quantities of tris(hydroxymethyl)amino- ' groups, linked by alkylene or 'alkylene and hy droxylated methylene groups. A speci?c com pound which may be used to illustrate ourv inven tion has the following structure: methane at 100° for 3 hours with no solvent and with. frequent ‘ stirring. The yellow glue thus formed was dissolved in hot alcohol and the solu tion was acidi?ed with hydrochloric acid. The precipitatev which formed on cooling was recrys stallized from aqueous alcohol. (For constants, see Example 1'.) 110cm ' 7 onion , nocHroNnomoHoHomNno-piimii ‘7 noon, ‘ ' cmon ‘ This compound, like all other compounds covered 4.0 by this invention is extremely soluble in water and also forms very soluble salts; as the dihydro " EXAMPLE 3 71.3-61.9 [tris (hydroxymethyl) methyldminol -2-proi , , panol _ chloride. Due to its high solubility and tothe ;(H0cH2)scNncrigcnoncnzNncwmon), hydroxyl groups and the secondary amino groups, ’ ‘The ‘free base,v ~1,3'-bis[tris(hydroxymethyl) by this inventiom may be combined with other Idium chloride, was prepared by treatment of the :dihydrochloride, in‘ methyl alcohol, with the cal-. this compound, like the other compounds covered 1 45 - methylaminole2-propanol, mixed with a little so less soluble substances to form new products of intermediate solubility. - ‘ ' ' ' 'culated quantity'of sodium methylate, re?uxing, ' As illustrative of the methods used to prepare 50 cooling; and-‘?ltering off the sodium chloride and jevaporatingto a'syrup. Also, the free base was compounds covered by our invention, we give the I 2,408,096 3 4 prepared for analysis from the dihydrochloride by prolonged heating with excess silver carbonate, removal of dissolved silver with hydrogen sul?de, and removal of colored impurities by repeated at 160.5-162°. Calculated for C14H3406BI‘2N2: Br, 32.87%. Found 32.10%. EXAMPLE 7 1 -diethanoZamino-3-tris (hydroxymethyl) meth solution in absolute alcohol and treatment with ylamino-Z-propanol dihydrochloride anhydrous acetone. Finally, by evaporation of the oily lower layer, the free base was obtained as an oil. Calculated for CnHzvOqNz: N, 9.40%. (HOCHZCHZ) 2NCH2CHOHCH2NHC (CI-120E) 3.2HC1 A mixture of 10.5 grams of diethanolamine (0.1 Found, 9.41%. mole) and 9.3 grams of epichlorohydrin (0.1 10 mole) was stirred well, the temperature being EXAMPLE 4 1,2-bis [ tris (hydroxymethyl) methylcminol ethane kept around 30°. After the initial exothermic re dz'hydrobromz'de ' action ceased the mixture was left over night at room temperature. The clear viscous liquid was extracted with ether. The ether insoluble prod A mixture of 12 grams of tris(hydroxymethyl) - 15 uct was added to 12 grams of tris(hydroxymeth aminomethane and 20 ml. of freshly distilled yl) aminomethane (0.1 mole) and 50 ml. of ethyl ethylene bromide was heated in a round bottom alcohol and the mixture was heated under re flask equipped with an air condenser, on an oil ?ux on a water bath for 6 hours. The reaction bath at 180° for 4 hours. A light brown colored mixture then was acidi?ed with concentrated hy glue resulted. The excess ethylene bromide was 20 drochloric acid. An oil was thrown out by the removed by extraction with ether. The residue addition of absolute alcohol, acetone and ether. was puri?ed by recrystallization from alcohol. This oil was converted to a semi-solid by solution The product, 1,2-bis[tris(hydroxymethyl) methyl in aqueous alcohol, treatment with anhydrous aminolethane dihydrobromide, melted at 205 acetone and allowing the lower layer, after evap 206°. Calculated for C10H26O6BI'2N2Z Br, 37.16%. 25 oration, to stand in a vacuum desiccator. Final Found, 37.09%. ly, puri?cation was eii’ected by extraction with EXAMPLE 5 hot absolute alcohol. Melting point, 139441". 1,3-bis [trz‘s (hydromymethyl) methyZamino-l pro Calculated for C'uI-IzaOeClzNz: Cl, 19.96%. Found, ' pane dihydrobromide (HOCHZMCNHCHZCHQCHZNHC(CH2'OH).Q.2HBr 30 A solution of 24 grams‘ of tris(hydroxymethyl) - 19.55%. EXAMPLE 8 1 - 'ethylethanolamino - 3 -'t1‘2's (hydroxymethyl) - aminomethane (0.2 mole) and 10 grams of tri methylene bromide (0.05 mole) in 150 ml. of alco methylammo-z-propanol dihydrochloride HOOHZOHACZHQNCHQGHOHCHzNHC(CHgOH)3.2HCl hol was heated under re?ux ‘on a water bath for 35 Ethylaminoethanol was reacted with an equi 6 hours. On standing over night, needle like molar quantity of epichlorohydrin at a temper-, crystals of (HOCHz) 3CNI-I2.HB1‘ were formed. ature below 30°. The condensation product thus These were ?ltered off and the ?ltrate was made formed was heated with an equimolar amount of distinctly acidic with hydrobromic acid. The acidic solution was evaporated to low volume to 40 tris(hydroxymethyl) aminomethane for 8 hours remove most of the water. The gummy residue - on a water bath and the mixture was acidi?ed with hydrochloric acid. Repeated attempts to was dissolved in hot absolute alcohol and treated recrystallize from alcohol failed to yield a solid with an equal volume of anhydrous acetone. Two but the light pink colored glue analyzed fairly layers were formed. The lower layer was sepa rated and triturated with a mixture of equal vol 45 satisfactorily. Calculated for C11H28O5C12N2! Cl, 20.90%. Found, 19.74%. umes of absolute alcohol and anhydrous acetone, until crystalline. The solid, 1,3-bis[tris(hydroxy EXAMPLE 9 methyl) methylamino] propane dihydro'bromide, on three recrystallizations from alcohol, melted at 170-171°. Calculated for C11H2806B1‘2N22 Br, at 35.98%. Found, 35.25%. EXAMPLE 6 1,6-bis [iris (hydromymethyl) methylaminlo ] hexane wy’ -Bis [trz‘s(hydro:cymethyl) methylaminol 41m pyl ether dih'ydrochloride (HOOHz) aCNHCHzCHzCHzO CHzCHaOHzNHC (CHZOH) 3.2K C A mixture of 17 grams of rm1’-dichloropropyl ether (01 mole) and 24 grams of tris(hydroxy methyDmethylamine (0.2 mole) in 100 ml. of al dihydrobromide 55 cohol was heated over night at 110°. The alco holic solution was acidi?ed with hydrochloric acid and the precipitated tris(hydroxyrmethyl) methyl A mixture of 48.4 grams of tris(hydroxy amine hydrochloride was ?ltered off. Repeated methyl) aminomethane (0.4 mole) and 24.4 grams evaporations, solution in absolute alcohol, treat of hexamethylene bromide (0.1 mole) was re 60 ments with anhydrous acetone and ?nally treat ?uxed with mechanical stirring until a homo ments with anhydrous ether were necessary to geneous mixture'was obtained. The brown glue remove all of the unreacted amino-alcohol hy thus formed was dissolved by re?uxing with 300 drochloride. Finally, the product 'y,'y'-bis[tris ml. of 95% alcohol. ‘The alcoholic solution was (hydroxymethyl) methylamino] -propyl ether hy made strongly acidic with hydrobromic acid and 65 drochloride was obtained as an oil, slightly im most of the alcohol was evaporated off. The pure. Calculated for C14H34O7C12N22 chlorine residue was treated with absolute alcohol and 17.16%. anhydrous acetone to yield crystals of impure (HOCHz)3C1\II-I2.H1Br, melting at 128-132°. The An attempt to prepare [ELK-bis [tris(hydroxy methyl) -methylaminol -ethyl ether dihydrochlo ?ltrate was treated with three volumes of anhy 70 drous acetone. An oily layer was formed. This lower layer was triturated with absolute alcohol and anhvdrous acetone, yielding a solid melting at 150-155". On recrystallization from 95% al-, ride in a similar way from B,B'-dichloroethyl ether and tris(hydroxymethyl)l-methylamine was cohol and anhydrous acetone, the product melted Found 16.30%. ' unsuccessful but 4-tris(hydroxymethyl) methyl morpholine hydrochloride, melting at 184-185° was obtained. 15.57%, Calculated for CsHiaO4ClN: Cl, Found, 15.59%. A ’ ' ' 2,408,096 6 5 The compounds to which our invention ‘relates TABLEI' possess certain novel properties respecting the solubilizing action on-various cations, in alkaline solution. ' r ' _ , _ . I 4 _ Cation solubtlization vwith 1,3-bis 'tris'mydroryé methyl) methylamino-z-propanol ~ As is well known, ferric hydroxide and some I ' - basic salts of the ferricion'are ‘extremely insolu; ble. Aqueous solutions containing'ierrous com; . Molar concentrations . mine Gabon pounds, in contact with air or‘dissolve'd oxygen‘, .0 mm alcohol ' y roxl e (and results)1 readily form insoluble ferric compounds, even 0.5 0. 5 0. 5 when rate ofthe oxidation solutionsincreases are distinctly as the‘acidic alkalinity and the in-. creases. Thus the clogging of iron pipes with rust is a serious industrial problem. Certain polyhydroxy compounds, such as the sugars, tend to hold iron in solution in alkaline medium, but V 0.5 0.5+ 0. 5 30. 5-} 0. 5 0. 5+ 0. 5 0.15 0. 25 0. 5 0.5 8.0£ 8. 0+ 4 8. 0d: 50. 5:1: ll2.51 ..... __ 0. 5* 0. 5+ O. 5 0. 5+ 2. 5+ 2 8. 0+ 2. 5+ 8. 0+ 0.5 00.5 ....... __ O. 25 0. 5 0. 5+ 2. 5+ 8. 0+ 0. 5 0. 5 0. 5+ - 2. 5+ 7 8. 0d; Cd++ ______________ . . these sugars, due to their reactivity, decompose , 2.5+ 2. 5+ 2. 5+ in alkali, particularly when warmed. Our poly-i 1 Failure to precipitate after approximately two hours is indicated hydroxyamines are much more stable toward al—' kali than are the sugars and alkaline solutions is used to_indicate initial solubilization but the formation of a pre by “+”. Immediate precipitation is indicated by “—-" and “:l:" cipitate within twohours, usually within a few minutes. of these compounds have high solvent action on 1 Precipitates within a few minutes; ferric hydroxide. For example, ferric hydroxide did not precipitate when alkali in excess was added to a solution approximately 0.1 molar in 5 It‘ air is present, a wine color starts to form almost as soon as the amino alcohol and Mn++ are mixed. When the air was displaced by Pyrofax gas, a clear solution was obtained which gradually be Fe+++ and 0.5 molar in 1,2-bis [tris(hydroxy came wine colored and ?nally purple. Also, a precipitate formed fairly readily, particularly in the solution containing excess alkali. ' methyl) -methylaminol ethane. Also, under ap 9 Bluish colored precipitate in deep blue solution. proximately the same' conditions, 1,3-bis [tris (hydroxymethyl)methylamino] propane, 1,6-bis '[tris(hydroxymethyl)methylaminol hexane, 1 tris(hydroxymethyl) methylamino-B-diethylami no-2-propanol and 1-tris(hydroxymethyl)meth ‘ 7 Precipitate, on standing. Since all of the polyhydroxyamines listed above proved to have solubilizirig action on cer :30 tain cations," in ‘alkaline solution, several ‘more derivatives of trislhydroxyme'thyl) aminomethane ylamino-3-ethylethanolamino -V2 - propanol gave no precipitate of ferric hydroxideQ _ r were V 1,3-bis [tris(hydroxymethyl)methylaminol - 2 - hours at 100° there was a slight silicious precipi tate but none of ferric hydroxide. , and tested as solubilizing 1,6-bis [tris(hydroxymethyl) methylami no]-23,4,5~tetrahydroxyheirane chosen arbitrarily to illustrate the solvent action propanol gave no precipitate when treated with an equal volume of 10 molar sodium hydroxide. On being heated in av sealed Pyrex tube‘ for 2 synthesized agents. The above‘ concentration of 0.1 molar Fe+++ is not necessarily the limit of solubility, but is of our amino alcohols on ferric hydroxide. In some cases much higher concentrations of Fe+++ can be held in alkaline solution. For example‘, a solution 1 molar in Fe+++ and in - 7 3 The precipitate at this point may be partly due to some hydro chloride of the amino alcohol, present as an impurity. l cloudiness, initially. Increased precipitate, on standing. ’ I ' ' - (HOCHc) sCNHCI-Iz (CHOH) 4CH2NHC (CHzOI-I) a formed (as the dihydrobromide) by heating man; nitol dibromide with‘ slightly over four molar ‘quantities of tris(hydroxymethyl) aminomethane at in alcoholsolution in a sealed tube at 138° for ' 15 hours, had a solubilizing action on Fe+++, Bi+++, Mn++, Ni++, Co++, Cu++ and Cd++, when the molar concentration of cation, amino alcohol and-‘sodium hydroxide were re 45 spectively 0.l,-0.25 and 3.5. ‘This is not neces sarily the limit of the solubilizinglpower of the In the solubilization tests described above and in the tests which immediately follow, the amino . ' amino alcohol for Fe(Ol-I)s did not precipitate when Fe+++,‘ the above amino alcohol and ex alcohols were used as salts, the dihydrochloride cess sodium hydroxide were mixed in molar con or dihydrobromide, and were treated with excess centrations of 0.33, 0.25 and 3.5 respectively. sodium hydroxide solution, to set free the amino ' alcoh'ols. ‘ Many useful applications of our novel solubil izing agents will occur to those skilled in the, ' Solubilization tests were run with each of the amino alcohols listed above and with each oi.’ the various arts. Illustrative examples of ‘a few uses cations Bi+++, Mn++, Ni++, Co++, Cd++ are given. and Cu++. The molar concentration of cation, 55 amino alcohol and sodium hydroxide were re spectively 0.1, 0.5 and 3.0. (Note: Actually, 4.0 " The ability of the amino alcohols to hold fer ric hydroxide in solution, as illustrated particu larly with 1,3-bis [tris(hydroxymethyl) methylam molar quantities of sodium hydroxide were used, 1 inol-Z-propanol, should ?nd many important in . dustrial applications. One particularly useful but 1.0 molar quantity was used up in setting free the amino alcohol from its salt.) 7. In all cases, 60 application is in cleaning out boiler tubes. Not only does the above amino alcoho1 have a ten dency to‘ hold ferric hydroxide in ‘solution but a hot alkaline solution of it slowly loosens rust. As stated above, in the case of the solubilization In a boiler tube, the loosening of rust so that it of ferric hydroxide, the data given do notnec 65 may be blown out of the tube, is almost as much essarily represent the limits of solubility, but are value as its’dissolution. clear solutions or at most very slight precipitates were obtained. 7 ‘ given to show that solubilization of, certain cation hydroxides is a characteristic of the series of polyhydroxyamines covered by this patent appli Another useful application may be in the treat ment of syphilis. A solution of bismuth contain ing approximately 60 mg. of bismuth per ml. was cation. 70 prepared by warming freshly precipitated bismuth Table I gives values obtained with various ca- . hydroxide with a solution which was'approxi tions, using 1,3-bis [tris (hydroxymethyl) methyl-' aminol-2-propanol as solubili'zing agent, with various concentrations of cation, ‘amino alcohol and sodium hydroxide. ' mately 0.8 molar in 1,3-bis[tris(hydroxymeth yl)methylaminol-Z-propanol and in sodium hy ‘ droxide and by neutralizing with tartaric acid to 75 approximately a pH of 7.4 This solution was 2,408,096 7 '74-21grams of 1,3-bis[_tris (hydroxymethyl) meth ylaminol-Z-propanol dihydrochloride and 20 found to be stable to heatin a sealed tube at 125° for _30 minutes. . The compounds to which our invention relates have properties which indicate their usefulness grams of sodium hydroxide per liter, did not de posit free copper on a clean strip of iron metal in calcium therapy for in the therapeutic use of calcium it is desired to have a moderately low concentration of Ca++ but to'have a relatively immersed in it. high concentration of combined calcium in a the solution, with the iron strip as=cathocle, an adherent coating of copper was deposited on the However, when an electric cur rent, with a voltage of 1.6 and a current density of 0.14 ampere per sq. dec. was passed through form in which it can be utilized by. the, body. . Calcium gluconate is likely the most generally 10 iron. The ability of the polyhydroxyamines not only used form of calcium for intravenous injection to hold the copper in solution but also to prevent and it also is used extensively for oral admin the precipitation of. copper on iron and to hold istration. It usually is given in 10 per cent solu tion intravenously or intramuscularly. Since cal iron and various other cations in solution should cium gluconate contains approximately 9 per 15 prove of- great value in copper plating. The abil ity of our amino alcohols to hold a low concen cent of calcium, this corresponds to a content of tration of various other cations should likewise approximately 10 mg. of calcium per ml. of solution. prove of value in electroplating with other i metals. In preparing calcium for therapeutic use we The temperatures reported in this application employed the following procedure: Freshly pre; 20 cipitated calcium hydroxide was warmed with an are all on the centigrade scale. equimolar quantity of 1,3-bisltris(hydroxymeth— yl)methylaminol -2-propanol dihydrochloride in some of the products remained as oils for a long In our work with the polyhydroxyamine salts, time and were crystallized with great di?‘iculty. approximately 30 per cent solution. The aqueous solution was filtered from a slight residue and 25 It is quite likely that some of the products evaporated to a syrup. which we reported as oils eventually may be On neutralization to crystallized to yield fairly high melting sol physiological pH (7.4) with hydrochloric acid a ids. The constants reported are those ob clear solution was obtained with a relatively low tained by careful experimentation but since concentration of Ca++ and a total concentration of approximately 40 mg. of calcium per ml. Ace 30 slight traces of impurities frequently prevent the crystallization of a substance or lower the tic acid also was used to neutralize the basic melting point of a solid appreciably, we do not solution containing calcium. A solution can be limit our claims to substances with the exact made by the methods just described appreciably physical properties reported. more concentrated than 40 mg. of Ca per ml. A further use for which our compounds are 35 adapted is in the art of electroplating.v As is well , known, elements high in the electromotive series readily replace from solution the elements lower in the series. Thus, iron displaces copper readily We claim: . > 1. New compounds of the structure (HOCI-Iz) sCNI-ICHz (CI-IX) ZCHZNHC (CI-120E) 3 where X is taken from the group H and OH and 40 2 represents a number from zero to four, in and when it is desired to plate copper on iron, it clusive. , is customary to use a bath containing potassium 2. Salts of the compounds in claim 1. cyanide to lower the concentration of the copper 3. _A new compound of the structure ion in solution. The toxicity of the cyanide solu (HOCH2) sCNHCHzCHOHCI-IzNI-IC (CHzOH) 3 tion makes it desirable to use a substitute. In alkaline solutions of our pc-lyhydroxyamines, the 45 4. Salts of the compound of claim 3. concentration of Cu++ is extremely low. As il 5. The dihydrochloride of the compound of lustrative of this low concentration and of an im claim 3. portant industrial application of these polyhy droxyamines, We give the ‘following example: Asolution containing 25 grams of CuSO4.»5I-IzO, JOHN S. PIERCE. T 50 '. JOHN H. WOTIZ. '