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Patented Sept. 10,1946 “ 2,407,560 UNITED STATES PATENT orifice MANUFACTURE OF THEOPTICALLY ACTIVE ‘ FORMS OF PANTOTH‘ENIAC ACID ; Richard Kuhn and Theodor Wieland, Heidelberg, Germany, assignors to Winthrop Chemical Company, Inc, New York, N. Y., a corporation ’ _ "of NewYork ’ ' No Drawing. Application August 26, 1941, Serial No.1408,355‘.1 In.Germany August TO, 1940 3 claims. (c1. 260-284)‘ examples theparts being by weight, but it is not This invention relates to the manufacture of the optically active forms of pantothenic acid. Pantothenic acid, a vitamin of the B-vitamin restricted thereto: 7 ‘ Example 1 ‘- -. ‘ group, is theacid amide compound of ,a,'y-dihy—, ' 2 parts of all-pantothenic acid are dissolved in droxy-p,/3-dimethylbutyric acid‘ - and ?-alamne. ; ‘ a small quantity‘ of water and brought to a pH‘ It contains an asymmetrical carbon atom._ of 8.5 with baryta" water. A hot aqueous solu tion of neutralquinine ‘sulfate is carefully added to this solution, until all the'barium has just precipitated. The precipitate is then centrifuged If d,1-ee'y-dihydroxy-/3,p-dimethylbutyric, acid-r >lactone is used in. the synthesis of pantoy ' thenic acid as the starting material, the racemic d,1-pantothenic acid is obtained, the usual salts 10 off. ‘ The aqueous solution is concentrated under and derivativesof which are obtained in a non diminished pressure. crystalline state. It has, now been found that this racemate can easily be split up into the optic antipodes by preparing thereadily crystallizing quinine salt or cinchonidine salt’of the (Ll-panto thenic acid and by subjecting thepartial race mates to fractional‘crystallization. ‘In the case of the quinine salt the compound being more dif ?cultly soluble is the salt of the (—) —pantothenic acid from which the free acid may easily be sep arated in pure form. qFrom the quinine salt be-y ing more readily _. soluble the (+) -pantothenic acid is obtained by removing the quinine. In the case of the cinchonidine salts the salt of the dex After some time the syrup obtained begins to crystallize and upon grinding with acetone changes to a white powder of ?ne 15 crystals. This powder is‘ recrystallized several times from acetone-methanol‘ (l to 1) whereupon the quinine salt of the (i-) -pantothenic acid pre cipitates in form of colorless soft shining needles melting at ‘165 to 167° C. (Berl’s method)‘. ‘ 1 part of this quinine salt is dissolved in 10 20 parts of ‘water'and rendered alkaline to phenol phthalein with baryta water.- The quinine pre cipitated is removed by shaking out three times with chloroform and three times with ether. The barium is removed from the aqueous solution trorotatory biologically active pantothenic acid is 25 by adding sulfuric acid in the exactly required more difficultly soluble. The cinchonidine salt, quantity. After centrifuging off the barium sul therefore, is especially suited for the manufac fate, the aqueous solution is evaporated under ture of the biologically active (+)-pantothenic diminished pressure. Thereupon the free (—) acid. For the manufacture of the pure d-panto pantothenic acid remains as a syrup-like sub thenic acid it is sufficient to recrystallize once the 30 stance being readily soluble in water and alco mixture of both cinchom'dine salts. The brucine hols. The speci?c rotation is (a) D21=-26.7° in salt of the natural pantothenic acid has already water and (a) D24=-56.3° in methanol. been prepared. But it is amorphous like all The barium salt of the (—)-pantothenic acid other known salts and derivatives of the panto which is obtained “by neutralizing the aqueous thenic acid. It was, therefore, surprising, that solution with baryta water and concentrating in the quinine salt and the cinchonidine salt, which a desiccator, is a bitter tasting glass-like sub represent the ?rst crystallized derivatives of the stance being readily soluble in water and alcohol. pantothenic acid, crystallize so well, that a sep The speci?c rotation is (a)n24=-20.4° in water, aration of the antipodes is possible. Because of the rotation of the pantothenate-ion is calculated the good crystallizability of the salts it is not nec 40 therefrom to (a)n24=—26.8°. essary to use pure d,l-pantothenic acid as the The (+)-pantothenic acid is obtained as fol starting material; from solutions of the impure lows: reaction product as they are obtained during the The syrup remaining after the above-stated synthesis, the quinine and cinchonidine salts may reaction of 2 parts of d,l-pantothenic acid with 45 also be obtained. quinine sulfate and after evaporating the water‘ For the manufacture of the quinine and cin under diminished pressure is ground with 80 chonidine salts e. g. the free acid may be treated parts of hot acetone. After ?ltering off the qui with the calculated quantity of the alkaloid, or nine salt of the (—) —acid from the mixture while salts of the d,l-pantothenic acid may be reacted still hot, the acetone solution is kept for some with salts of quinine or cinchonidine, or esters of 50 pantothenic acid may be saponi?ed with quinine or cinchonidine. From the salts the optically active acids may be set free according to the methods usual for this purpose. time in the ice box. The quinine salt of the (-—) - acid which has precipitated is then ?ltered with suction and the mother liquor is evaporated under diminished pressure. The residue is re The invention is illustrated by the following 55 crystallized iour times from acetone or methyl 2,407,560 ethylketone while the more di?icultly soluble still warm solution. A quinine salt melting at 138 to 142° C. is obtained in form of white nee mate.’ Efficiency dles: (0L)D22=',—'98_°'.f (in relation _- '_to= (+)-pantotl'deni'c " ,7: - acid) =50,000,000 sbm. units (streptohacterium units) per gram. j units per gram. 7 , - . ‘all; In’ a prooes lfor the-ioiitic'al lzreslolntion of-a 10 tallization from a solvent comprising essentially a-vlower aliphaticke'tone the diastereomeric crys talline pantothenic acid salts of an alkaloid of '-'the group consistinglorf" quinine and oinchonidine. . , ."_ ‘72;: The ‘process-this? obtaining an alkaline metal f ‘ the (—)-acid the barium Salter-tile (+). (pantothenate-ion) =5o,0c0,o0o shiny. _‘ racemic pantothenic acid compound, the step ‘ Y which comprises separating by fractional crys aqueous barium hydroxide solutionJaSiSiEQLtGQTfOr- Y ' E?iciency ‘ units per gram for the (+)-pantothenic acid contained in the cinchonidine salt. The effi ciency is just twice as great as that of the'race parts are removed by ?ltering with suction the , Yield By 1decomposing part of quinine thesalt..' said ‘ quinine‘ v , salt _' , ‘with ' ‘(+) ‘pantothenate which comprises-forming the 15 crystalline‘cinchohidine'salts of» the (+)’ and of > ’. the;(;)l.~pantothenio ‘acidby reacting a CIA-‘pan If esters of ‘the. d,l-pant0theni‘c“acidiarertrea’o- " ' trithenicacidqcorri'pound with cinchonidine, sep ed with the calculated quantity of quim'ilein; ‘ aratinglthe diastereomeric crystalline cinchoni aqueous alcoholic solution, likewise the quinine ' dine pantothenates so obtained by fractional ' salts of-the antipodes are obtainedlafter evapo 20' crystallization from a solvent comprising essené tially a lower aliphatic ‘ketone, and converting ration of the solvent. They may ‘be separated . as indicated above. theoifnchonidine (+) pantothenatetherehyob-éj ' tained as the less soluble diastereomerl intoxan Example 2 solution "of 2 parts of bariurriédl-pahtothen icacid in 12 parts of methanol-are mixed while Warmwith a solution of cinchonidine sulfate. in alkaline earth-metal '(+ ) ‘pantothenate by double‘ * 26 decomposition With a "water-soluble alkaline; ‘metal earth base. i - The process ior obtaining an" alkaline earth methanol as long as barium sulfate precipitates. it metal £+) pantothenate which comprises‘form-? The mixture is centrifuged and the precipitate is ing’ the crystalline 'cinchonidine salts of the (+) washed twice with warm} methanol. The ineth 30; and of the ('—-)I pantothenic acid‘by reacting‘an an-ol solutions united are concentrated to a thin syrupv under diminishedrpressure whereupon the whole, mass crystallizes ‘after standingwfor some hours, The mixture of the two. cinchonidine salts is; dissolved in the just necessary" quantity of boil ing‘ 'methylethylketonei- , While cooling, the cin alkaline earth metal d,l-rpantothenate withil c'in-V chonidine sulfate, removing ‘the i'nsolubl‘e'allka-s line earth metal ‘sulfate, separating the‘, diastereli onieric crystalline-cinchonidine- pant'othenatesso ‘ obtained‘ by fractional crystallization from? a sol; vent com-prising essentially a lower aliphatic ke tone, and converting the‘ci-n'chonidine (+) pan tothenate-i thereby obtained as the-less .soluible diastereomer into an alkaline earth metal (+)- cho-nidine salt of the (+i)w—pantothenic acid ‘pre-, cipitatesiri vform of ?ne white needles; melting at 178 to 179° C. (Berl’s method). Yield 1.2 parts. Further- recrystallization does not change the pantothenate' by double decompositioniwithlai melting‘ point: - (0c) D1_8=—'-62.3° (water). water-soluble alkaline earth ‘metal base. T Y‘ -'I_‘he biological ei?ciency in the growing test according to Moller amounts to» 50,000,000; sbm. Y » ' ' - RICHARD KUHN'. 'I'HEODOR .- i - ‘ '