Патент USA US2407727код для вставки
Patented Sept. 17, 1946 r 2,407,726 UNITED STATES‘ PATENT‘ OFFICE - METHODS OF‘PREPARING ‘CHEMICAL ‘ PRODUCTS ‘ Lee Irvin Smitli,.Minneapo1is;Minn., and‘William. B.'Renfr0w; 51a, Charlotte, N; 0;,‘ assignors'to . Reg'ent‘s-of‘the ‘University ofiMinnesota; Minne apolis, Minn, a corporation-ofr‘Minnesotav N0 Drawing. ApplicationAugustZ,1941, Serial ‘No. 405,796‘ 7 3 Claims. 1 (01. 260-333)‘ 2' The present’ invention relates to'derivatives of theto'copherols'and related substances and to the method of preparing such derivatives. Contemporary advances in the knowledge of nutrition and‘medicine in'th‘e medical and vet erinary ?elds have developed the importance of . enttinvention' so as to‘ furnish-,after the‘?rst"rej— action, an acid. group capable. oi'reaction with a metal ‘ion to form a salt. In this present‘ invention;. it‘ has been‘ found? ' that the‘ desired compound can be prepared by ?rst proceeding through an. intermediate step, by treating a selected tocopherol‘ with a Grignard‘ reagent. such as methyl, ethyl or isopropyl maga substances having biological activity. Substances designated“ as the “tocopherols” have beenshown tube the primary compoundsexhibiting vitamin nesium iodide, bromide or chloride. .The; alkyl E activity and much WOI‘k' has been carried out 10 group of the Grignard reagent is preferably to ‘increase‘the' knowledge concerning these com chosen so that the alkane subsequently generated pounds for clinical and veterinary uses; To ac _ in the reaction will be volatilized at thetemperar celerate‘ the" accumulation of this‘ knowledge, standard‘test conditions-have been’ established to Thus, where the'methyl-Grignard reagent‘ is used‘, ' evaluate the‘ comparative strengths '- or V potencies 15 methane‘is liberated, similarly, Where'tlie‘ethyl‘ tures. used, and therefore‘ readily separated; of‘ test‘ materials‘by the use'of “standard” ani G-rignard is used,.ethaneiis liberated: If, the hy mals, usually white‘ rats; It has been'established drocarbon‘ liberated is‘ not readily volatilized',‘ it that results thus obtained on “standard” testtani mayineyertheless- be separated by’ use of. appro= mals may'normally' be projected‘ and applied to priate procedures‘. , other mammals” and’ to ‘ human beings ‘by‘ the ap 20 After reaction of. the tocopherol with the G'rig plication" of factors established by‘clinica‘l tests nardireagent; thereacti'on product is 'treated’iwith. the anhydride of‘ thepolybasic acid, which; re acts with the halo-magnesium derivative of‘ the relating“ torcompositions other than' those ex‘ hibiting vitamin E activity. . ‘ Extended clinical tests on human beings re tocopherol‘to thus form an ester salt. Thus, suc quire relatively long periods of'time and therefore the-mode of'utilization of" any medical‘or dietary improvement; whether- in the vitamin-?eld or'in other ‘medical or ‘dietary ?elds, maybe developed‘ only‘ after years of» study; but'this does ‘not‘pre cinic anhydride reacts with the halo-magnesium derivative of‘ the, t'ocopherol, inserting; itself‘ be. tween the magnesium halide and‘ the oxygen to which it is attached. By acidifying this product, such, as the' tocopherolsv and‘ their‘ derivatives formed in place of the magnesium halide. The free acidphaving ‘one group esteri?edwith theselected tocopherol', other hydroxy chroman or hy-‘ a1 free acidfhaving one acid group of the starting ' cl'ude- valuable ‘utilization of" speci?c ' materials 3 U (ii-basic acid- esteri?ed with the tocopherol is within" the purview‘ of. available information. Therefore, it is’ logical and proper't‘hat‘ considi erable Weight be given to ?ndings‘developed‘ih‘ the tests with “standardized” test" animals. ‘Co-pending application Serial No. 211,077, Patent 2.2452054; and"otherapplications, describe processesfor'synthesizingtocopherols; A further. droxy coumaran, is a new and useful interme ' diate which may be‘used-for. the‘ formation-of a invention, as described in this application, resides in: the-process‘ for making stableand' useful de rivatives of the‘tocopherols. It‘ is‘a'n object of the invention to prepare de rivatives‘of‘ the’tocopherols, which derivatives re tain' the biological activity of the primary t‘ocopherol‘itself, and yet assume various desirable physical characteristics which‘ assist in' utiliza tion of the compositions; A‘ further object'is to prepare a nonetoxiere action product‘ which is suitable for. clinical‘ use wide variety of further'compounds. Thus, it may bereacted with alkali metal salts orbases toform an ester'salt" of the polybasic acid, in which one, acid group has been. esteri?ed with tocopherol', and ‘the other converted to a salt. . This invention is illustrated by the'following example which, however, must. not be taken asv any limitation upon the. invention describediand claimed.“ Eztampl'e a-tocopherol‘ (4:91‘ g.) was dissolved in: ethyl ether" (50 c0‘.)1 and’. al 5:%- excess; based‘ on‘ the: tocopherol, of, propyl magnesium chloride‘in ethyl and‘ has" vitamin E activity substantially equiva ether" (5.3 cc., ZIOG‘N.) was added; After thor-A lentto the a-tocopherol‘content, on the molecu lar basis; but which has modi?ed chemicaLand physical‘ properties, particularly. that. of being a solid‘rather than a liquid. A further object is to provide a process for pre7 1.! ough- mixing of theforegoing reaction’ mixture, paring di-basic'l-acid anhyd'ride-reaction products of the tocopherol'sl ~ More speci?cally, one object is to prepare a at“ roomItemp'erature, a- solution of'su'ccinic an hydride-(Llllg, 10%excess) in dioxane; (1000:)“ Was- added‘la-nd' the ?'askl r-ins'ed’with anad‘diti‘onal . 1000; of di'oxane; The‘ reaction ‘mixture was then; stoppered and? allowed‘ to“ stand5 overnight; at’ room ‘ temperature, after which“ it‘ was‘ heated-ion a steam bath for four hours. 'It was then poured “ ' calcium salt of the acid succinate of a-tOCOphEI‘Ol, into water, the reaction mixture acidi?ed with A polybasic anhydride is required in the pres 60 dilute hydrochloric acid, extracted with ethyl 2,407,726 3 4 . groscopic solid that latherswhen shaken with water but is only very slightly soluble in water. The salts of ammonium, potassium, and chloro magnesium yield oils by a similar process. The ether and the ether solution dried, by introducing thereinto a solid drying agent. . The solution was then ?ltered to remove the drying agent and the ether evaporated from the ?ltrate. There remained 5.88 grams (97.2% yield) of barium salt is a solid. . the acid succinate of ‘it-tocopherol. This was then dissolved in methanol (25 cc.) Maleic anhydride,, phthalic anhydride, and ' glutaric anhydride form derivatives that closely resemble in physical properties the derivative and concentrated ammonia (1 cc.) was added, from succinic acid. . followed by the addition of a solution of calcium The invention is applicable to such raw ma chloride in methanol (13 00., 10%, 100% excess). 10 terials as the natural 11-, c- or gamma-tocoph A voluminous precipitate formed. The mixture erols, or to synthesized a-tOCODheI‘O], or xylol was thoroughly stirred for ten minutes and more tocopherols, or to other hydroxy chromans or hy concentrated ammonia (3 cc.) added. After fur - droxy coumarans and similar compounds.’ ther stirring, the precipitate was allowed to settle, Many obvious variations may be made in the the liquid decanted off and the precipitate 15 invention herein illustrated and described with washed with acetone. The solid is dried for a out departing from the spirit of the invention short time at 100° C. in a vacuum, after which claimed. 1 . it was dissolved in hot dioxane (100 cc.) and re We claim: precipitated by pouring the solution into water 1. The process comprising reacting a com (150 cc.). The liquid was decanted off, the solid pound selected from the group consisting of ,hy washed with acetone and dried in a vacuum droxy chromans and hydroxy coumarans with a ‘ desiccator. The solid was dissolved in a mini Grignard reagent, reacting the resultant mix mum amount of hot dioxane and the hot solution ture with a polybasic acid anhydride, and acidi_-. ?ltered, after which the ?ltrate was cooled. A . voluminous precipitate formed. Two volumes of 25, fying the reaction mixture. com- ' > 2. The process comprising reacting acetone were then added, mixed thoroughly and pound selected from the group consisting of hy the liquid decanted off. The solid remaining after decanting was washed with acetone and , droxy chromans and hydroxy coumarans with a Grignard reagent, reacting the resultant mix, dried for a short time in a vacuum at 100° C., dissolved again in a minimum amount of hot di 30 ture with a polybasic acid anhydride, acidifying oxane and allowed to crystallize from the cooled the reaction mixture, and recovering. the’ 'acid polyhydric acid ester of the selected starting ma-" liquid. The solid was then washed with acetone ‘ and dried at 100° C. underreduced pressure. 3, The process comprising reacting a com weighed 44 grams (‘71% yield) and melted at 214-215” C. 35 pound selected from the group consisting of hy terial. I a droxy chromans, and hydroxy coumarans witha The product is a white solid, readily soluble Grignard reagent, reacting the resultant mixture in ethyl ether and ligroin; moderately soluble in with a polybasic acid anhydride, acidifying the alcohol; soluble in hot dioxane and sparingly reaction mixture, and reacting the acidi?ed prod soluble in cold dioxane; insoluble in water and ' acetone. Combustion analysis shows good cor 40 uct with a metallic base. 4.‘The process comprising reacting a. com relation between theoretical and observed analy pound selected from the group consisting of hy-' sis, as shown in the following table: Carbon , Per cent Calculated for (CaaHsaOshC? _____ .._ 72. 10 Hydro- - gen Calomm Per cent 9. 75 Per cent 3. 45 droxy chromans, and hydroxy coumarans witha Grignard reagent, reacting the resultant mixture with a. polybasic acid anhydride, acidifying the reaction mixture, reacting the acidi?ed product with a metallic base, and recovering the salt 01'‘ the acid polyhydric acid ester- of theselected starting material. Rigorously conducted vitamin E assays with 50 5. The process comprising reacting a tocoph-v Found ____________________________ __ 72. 27 9. 70 ,3. 37 , rerol with a Grignard reagent, reacting the re-, “standard” test animals shows that the com ‘sultant mixture with succinic anhydride, and pound is fully equivalent to a-tocopherol on a acidifying to form the acid succinate of the’ molecular basis, and the compound is effective in tocopherol. _ increasing reproduction when used as a dietary 6. The process comprising reacting a tocoph 55 supplement in the food mixtures fed to fowls ero1 with a Grignard reagent, reacting the re such as chickens, ducks, turkeysand the like and sultant mixture with succinic ahydride, acidify- . food mixtures for fur bearing animals such as ing, and reacting the resultant product with foxes and mink. For such uses, the calcium suc compound presenting an available reactive cal—_ cinate ‘salt of tocopherol is especially desirable in cium ion, to form the calcium salt of the acid , that, it is stable in air, soluble in fats and in succinate of the tocopherol. soluble in water. Other metallic‘salts of any of the metals may be prepared in an ahalogous fashion by neutraliz ing the polybasic acid ester of the selected tocoph erol by the appropriate metal base or by treat ing the ester with selected salts of'appropriate ' metals. Where the ?nished product is used for medical or dietary purposes, the metal selected for formationrof the salt is, of course, non-toxic. 7. The process comprisingreacting izr-tocoph} erol with an valkyl magnesiumv halide wherein the‘ alky1 group corresponds to an easily volatilized -. alkane, reacting the resultant mixture with suc cinic anhydride, acidifying the mixture, and re? acting the resultant acid succinate ester of a tocopherol with calcium halide under alkaline conditions to form the corresponding calcium For other purposes where the matter of toxicity 70 salt of the acid succinate of u-tocopheroh is unimportant, other metals may be used. LEE IRVIN SMITH; The sodium salt so prepared is a slightly hy WILLIAM RENFROW, JR.‘ "