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United States Patent Office Patented June 2, 1964 3,135,788 United States Patent Office Patented June 2, 1964 1. 2 tine is, if pure, a very stable substance. Further we 3,135,788 PREPARATION OF D-CARNT, NE HYDROCLO. found out that by any conventional method for syn RE FROM TRMETHYLAMNE HYDROCLC). thesizing carnitine, a large amount of by-products are un RDE AND EPHALOGENGHYORN avoidably formed, and that the instability of carnitine funzo Noguchi, Kanazawa, and Naoichi Sakota, Nishi would be ascribable to the presence of such by-products nomiya, Japan, assignors to Nihon Zoki Seiyaku Kabu which are practically impossible to remove from carnitine shikikaisha, Osaka, Japan, a corporation of Japan even by recrystallization. As a logical consequence, it No Drawing. Filed July 18, 1960, Ser. No. 43,275 ensues that a synthetic method for preparing carnitine Ciainas priority, application Japan Sept. 28, 1959 must satisfy the following three conditions; namely, i0 Claims. (C. 269-53) O (1) Carnitine should be produced in a high yield, This invention relates to a method for the preparation (2) The amount of by-products accompanying through of DL-carnitine hydrochloride, and in particular, to a all the steps should be minimum, novel synthetic method for preparing DL-carnitine hy (3) Said by-products should be readily removable from drochloride of high purity in a good yield. the final product, carnitine. The chemical nomenclature of said DL-carnitine hy 15 We have accomplished, as a result of numerous experi drochloride is DL-y-trimethyl ammonium-6-hydroxy ments, the method of this invention which satisfies the butyrate hydrochloride represented by the following con above three requirements. The method of this invention comprises a reaction of stitutional formula. epihalogenohydrin having the general formula of CH3 20 CH-CH-CH2X Y / CEG-CH-CH(OID-CH-C OOH O CHyd (where X denotes Cl, Br or I atom) upon trimethylamine In the following description of the specification, for hydrochloride to produce 3-halogeno-2-oxypropyl tri brevity's sake, the conventional designation of simple 25 methyl ammonium chloride which is represented by the "carnitine” will be used instead of the rather lengthy DL general formula carnitine hydrochloride. Carnitine is a substance that was found in the muscle extract of mammal by Gulevisch and Krimberg (Z. Physiol. Chem. 45, 326), and by Kutscher (Z. Untersuch. 30 (where X denotes Cl, Br or I atom), then a reaction of Nahr. u. Genussm., 10,528) in 1905. The constitutional this 3-halogeno-2-oxypropyl trimethyl ammonium chlo formula of carnitine was determined by Tomita and others ride upon NaCN or KCN to produce 3-cyano-2-oxy in 1927. In 1952, carnitine was proved by Carter et al. propyl trimethyl ammonium chloride, and then, a hy to be the same substance as vitamine Br, a new member drolysis of said 3-cyano-2-oxypropyl trimethyl ammonium of vitamine B group, which has been discovered by 35 chloride with under normal pressure to produce carnitine Fraenkel et al. in 1948. which is represented by the formula Numerous studies have been made on the physiological and pharmacological actions of vitamine BT, i.e. carnitine. (CH)-CH- H-CH-COOH The preparing methods of carnitine may be divided into Cl OH two classes, i.e. an extracting process from natural mate 40 Carnitine produced by the above method may, if desired, rials and a chemical synthesis. A number of methods be refined by treating with glacial acetic acid to remove have been proposed up to the present. The extracting the reaction by-products as will be later described. The process from natural materials, however, does not go be reaction scheme of the method of this invention is as yond the laboratory scale. On the other hand, the syn follows. thetic method which is now considered to be successful 45 (CH3):N-HC1 + CH-CH-CH2X - to a certain extent comprises, however, many difficulties, 3 / 2 Such as, an extremely low yield and a large amount of O by-products, which make it practically impossible to ob e.g. KCN tain a product of high purity. The method by Friedman (CH)-N-CH-I-CE.X a-3 50 Cl OE IBiochem. Preparations, 6 (1958) is an example of the hydrolyze with extracting processes from natural sources. According to (CH3)3N-CH-CH-CHCN --> this method, carnitine is isolated from beef extract by - e.g. Cl treating with organic solvents, ion-exchange resins and i OH other agents, but the yield of carnitine is only about 7 g. (CH)n-CH-H-CH,C O OE based on 450 g. of beef extract. The method devised by 55 Cl OE Carter and Bhattacharyya J. Amer. Chem. Soc., 75, 2503 (1953) is an example of the synthetic methods. Accord According to the method of this invention, carnitine can ing to this method, carnitine is to be synthesized from be obtained with yield of ca. 85% in the preparation of benzaldehyde and epichlorohydrin, through several steps. a crude product, and ca. 75% in case of the refined prod The final yield of carnitine is but ca. 20-25%. The method 60 uct. Carnitine of high purity may also be obtained, be by Dechamps and others Compt. rend., 283, 826, cause, as is evident from the reaction mechanism, the (1954) is another example of a synthetic method, in by-products are minute in amount and their removal is which y-chloro-5-oxybutyronitrile that has been prelimi quite easy. narily synthesized is made to react with trimethylamine, As is apparent from the above explanation, the object and the reaction product hydrolzed under pressure to pro 65 of this invention is to provide a method for preparing duce dicarnitine, but the yield is only ca. 20%. stable carnitine of high purity in a good yield. We, the inventors of this invention, have searched for A still another object of this invention is to provide a a better synthetic method of producing carnitine, and have novel method for synthesizing carnitine which is char inquired into the origin for the instability of carnitine. acterized by the minuteness in amount of the by-products This led to a discovery of the fact that the instability is 70 formed during the process of preparing carnitine, and by not an inherent nature of carnitine itself, but is derived the easiness with which these by-products can be removed from the impurities still held in carnitine, and that carni from the final product, carnitine. 3,135,788 3 - 4 - A still further object of this invention is to provide an as the hydrolyzing agent at approx. 100 C. under normal effective method for removing by-products from the carni pressure eases the hydrolysis, producing but an extremely. time produced. minute amount of by-products including crotonobetaine. The detailed description of the method of this inven We also discovered that the purpose could be attained tion will be given hereinafter in the order of producing 5 as Well by using an acid of ca. 6N and by heat-treating StepS. at approx. 130 C. for several hours provided the hy (1) : Epichlorohydrin, epibromohydrin or epiodohydrin drolysis be carried out under normal pressure. There is preferred as epihalogenohydrin to be used in the method fore, to obtain a carnitine of high purity, a hydrolysis at of this invention. The reaction of epihalogenohydrin about 100 C. under normal pressure with a concentrated with trimethylamine hydrochloride may be accomplished. O acid or a hydrolysis at about 130 C. under normal pres by either directly mixing the two, or by carrying out the Sure with an acid of ca. 6 N is necessary. The main by reaction in the presence of an organic solvent such as products in this third step are ammonium chloride (when methanol- or ethanol or ; in an aqueous solution. The , hydrochloric acid is used as the hydrolyzing agent) and reaction may be effected at 30-50 C. under normal pres crotonobetaine. The hydrolysate may be recrystallized sure, or at a higher temperature under pressure. 5 with methanol or ethanol to separate, the by-products 3-halogeno-2-oxypropyl trimethyl ammonium chloride from carnitine, but we discovered that, by treating the represented by the general formula : hydrolysate with glacial acetic acid in the manner as de scribed below, not only ammonium chloride, but also (OH)n-CH-CH(OH)-CH.xC1. crotonobetaine could be completely removed. The de 20 tail of this step. follows. - (where X denotes Cl, Br or I atom). which will be ob-, The hydrolysate. obtained by hydrolyzing with hydro-. tained by the above reaction is a novel and unknown chloric acid as described above may be either concen-: substance, which is not referred: to in literature. The trated in vacuo to drive out the greater part of free hy yield is 90-95%. - - - drochloric acid, or neutralized by alkali, e.g., sodium hy (2) KCN or NaCN is recommendable as the cyano 25 droxide of ca. 6 N, and then the hydrolysis product thus compound to be brought into reaction with said 3-halo treated is, after decolorizing with active charcoal, concen geno-2-oxypropyl trimethyl ammonium chloride. The re trated to dryness under reduced pressure. The dried action of 3-halogeno-2-oxypropyl trimethyl ammonium. product is now treated with hot glacial acetic acid. Filter chloride with the -cyano compound may be effected by ing off insoluble ammonium chloride and crotonobetaine, - adding the cyano compound dissolved in a possibly small 30 and cooling the mother liquor, crystals of carnitine will quantity of water to an aqueous solution of 3-halogeno separate out. By separating the crystals, washing with 2-oxypropyl trimethyl ammonium chloride, or, the reac ethanol, drying under reduced pressure, and then recrys tion may as well be carried out in an organic solvent such tallizing with methanol, carnitine of approx.
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