Патент USA US2390499код для вставки
2,390,499 ’ Patented Dec. 11, 1945 UNITED STATES PATENT OFFICE 2,390,499 PREPARATION OF CALCIUM PAN TOTHENATE Gustaf H. Carlson and Sidney It. Sa?r, Pearl River, N. Y., assignors to Lederle Laboratories, Inc., New York, N. Y., a corporation of Dela ware No Drawing. Application January 17, 1942, Serial No. 427,178 4 Claims. (Cl. 260-534) nium or calcium amide with s-alanine in an al This invention relates to an improved method coholic medium and heating at relatively low temperature until solution is e?ected. Temper atures of from 75° to 100° C. are usually sum for the preparation of calcium pantothenate. Calcium pantothenate has been prepared in the past by a number of methods, such as for example fusing calcium B-alanate with why droxy-p,p-dimethyl-'y-butyrolactone, by reacting cient, the temperature being somewhat depend B-alanine with the lactone in aqueous calcium reaction medium. The a-hydroxy-?,p-dimethyl 'y-butyrolactone is then added to this alcoholic ent upon the particular alcohol employed as the hydroxide, or by reacting p-alanine, calcium hy solution and a reaction takes place at room tem- _ droxide, and the lactone in an aliphatic alcoholic medium. These previous or older methods em 10 ployed for producing calcium pantothenate re quire rather elaborate puri?cation steps and perature resulting in the production of calcium pantothenate. If desired, this step may also be when the aqueous solutions are employed, it is necessary to carry out tedious evaporations and carried out at lower temperatures or tempera tures up to about 100° C. may be employed. The calcium pantothenate thus produced can be re dried salt. It is an object of the present inven tion to provide a method for preparing calcium of the alcohol, or by dilution of the alcoholic so lution with ether, acetone, or the like, to cause frequently prolonged desiccation of the di?icultly 15 covered by direct crystallization, by evaporation precipitation. When the precipitation method is utilized for recovering the calcium pantothenate, cium pantothenate. 20 it may be puri?ed by crystallization from a suit able aliphatic alcohol, such as methyl or ethyl In accordance with the present invention we alcohol. have discovered that calcium ammonium or cal The invention will be described in greater de cium amide can be reacted with ?-alanine under tail in conjunction with the following specific suitable conditions to produce calcium ,a-alanate, example. It should be understood, however, that and in a further step reacted with oz-hYdI'OXY the example is given merely by the way of illus p,p-dimethyl-'y-butyrolactone in an alcoholic tration and the invention is not to be limited to medium to produce calcium pantothenate. In the details set forth therein. carrying out the reactions, the calcium ammoni um or calcium amide is preferably reacted with Example 1 pantothenate in good yields and under condi tions which facilitate the recovery of a pure cal p-alanine in an alcoholic medium under substan 30 tially anhydrous conditions and then adding the lactone to this solution results in the production Calcium (1 g.) was dissolved in 30 cc. of liquid ar'ii'moni?t —80° 0., most of the ammonia was of calcium pantothenate in a substantially an distilled and the residue was treated with 50 cc. hydrous form. When desired, the p-alanine and of n-butanol. After most of the ammonia had ¢-hydroxy--,l9,,B-dimethyl - 'y - butyrolactone may 35 ?rst be mixed in the alcoholic medium and sub sequently treated with calicum ammonium or calcium amide to result in the production of cal cium pantothenate. I Similarly, the calcium amide may be ?rst added to an alcoholic solu tion of the lactone and this solution subsequently treated with p-alanine to result in the produc distilled, the mixture was maintained at 80° C. for thirty minutes and, after addition of 4.45 g. of ?-alanine, the mixture was heat-ed another half hour. The insoluble materials were ?ltered off and the clear ?ltrate was treated with 6.5 g. 40 of 1--a-hydroxy-,B,/3-dimethy1 - 'y - butyrolactone (a=—48.3°). After three days, solvent was dis ' tilled in vacuo and the gummy residue was dis solved in 30 cc. of methanol. During forty-eight hours the solution deposited 2.6 g. of: crystalline tion can be produced by reacting metallic calcium 45 calcium pantothenate, m.p. 185-187" C. (uncor tion of calcium pantothenate. The calcium ammonium utilized in our inven rected). Analysis calculated (CoHmOsNhC'a: with liquid ammonia and removal of the excess Ca, 8.41. Found: Ca, 9.30. “In water solution the ammonia by distillation. The calcium ammo salt showed a rotation of (a)=+24.1° and was nium thus produced can be used directly in the completely active in a bioassay with Lactobacil subsequent steps or it may be converted to the amide by heating and the calcium amide used in 50 lus casei E. Similar results have been obtained employing the subsequent steps. It is to be understood, other alcohols instead of n-butanol, and it is ob therefore, that calcium ammonium or calcium vious that our invention may be carried out uti amide may be used interchangeably in carrying lizing as the reaction medium any ordinary ali out our invention. In general we prefer the method which comprises mixing calcium ammo 65 phatic, aromatic, or heterocyclic alcohol or‘any 2 2,390,499 mixture of such alcohols. The aliphatic alcohols suitable for carrying out our invention include ious diluents. The preferred diluents for this op eration are acetone, ether, and ethyl acetate. The term “alcoholic medium" employed in the the normal and branched chain compounds, such as methanol, isopropyl alcohol, butanol, and the speci?cation and claims includes any one of the like. Similarly, the polyhydroxy aliphatic alco 5 alcohols mentioned above or mixtures thereof. hols, such as ethylene glycol, glycerine, and prop We claim: ylene glycol may be employed. The ether alco 1. A method for producing calcium pantothen hols, cellosolves, ethylene glycol monomethyl ate which comprises reacting a substance of the ether, the corresponding butyl ether, phenyl and group consisting of calcium ammonium and cal benzyl ethers, are likewise satisfactory. The car 1 0 cium amide with ?-alanine in an alcoholic me bitols, diethylene glycol monomethyl ether, the dium and subsequently adding a-hydroxy-?,?-di corresponding butyl ether, and the like, may also methyl-'y-butyrolactone to the alcoholic medium. be employed. The alicyclic compounds, cyclopen 2. The process which comprises reacting a sub tanol, cyclohexanol, fenchyl alcohol, menthyl al cohol, and the like, are satisfactory. The aro matic, arylaliphatic, and heterocyclic alcohols that may be employed include those such as ben zyl alcohol, phenyl ethyl alcohol, naphthyl meth yl alcohol, furfurol, tetrahydrofurfurol, and the stance of the group consisting of calcium ammo 1 5 nium and calcium amide with p-alanine in an alcoholic medium to give calcium p-alanate. 3. The process which comprises reacting a sub stance of the group consisting of calcium ammo nium and calcium amide with p-alanine in an like. The preferred alcohols for carrying out the 0 aliphatic alcoholic medium to give calcium # process are the lower aliphatic alcohols such as 2 alanate. methyl alcohol, n-butyl alcohol, and ethyl al 4. The process which comprises reacting a sub cohol. Similarly, it should be understood that the cal stance of the group consisting of calcium ammo nium and calcium amide with ?-alanine in n cium pantothenate may be isolated by direct crys 6 butanol. tallization from the reaction medium by evapora 2 tion of the reaction medium or by precipitation from the reaction medium by dilution with var GUSTAF H. CARLSON. SIDNEY R. SAFIR.