ffice
`
`2,870,198
`Patented Jan. 20, 1959
`
`United States Patent
`1
`
`2,870,198
`PRODUCTION OF CHOLINE SALTS
`Howard C. Klein, Brooklyn, N. Y., and Walter Anthony
`Di Salvo, North Arlington, and Rofand Kapp, Newark,
`N. J., assignors to Nopco Chemical Company, f'I:?r•
`rison, N. J., a corporation of New Jersey
`No Drawing. Application March 22, 1954
`Serial No. 417,972
`9 Claims.
`(Cl. 260-501)
`
`2
`the desired acid with the choline to produce the desired
`choline salt.
`The ethylene oxide and the trimethylamine can be in(cid:173)
`troduced into the reaction mixture in any desired manner.
`5 Thus gaseous trimethylamine · can be introduced into an
`aqueous alcohol solution of ethylene oxide or, con(cid:173)
`versely, gaseous ethylene oxide can be introduced into an
`aqueous alcohol solution of trimethylatnine. Also, if de(cid:173)
`sired, gaseous trimethylamine and gaseous ethylene oxide
`10 can be introduced simultaneously into the aqueous al~
`coho!. In addition, separate alcoholic solutions of ethyl~
`ene oxide and trimethylamine may be admixed with each
`other with one or both of the solutions containing water,
`the total amount of water in the reaction mixture being
`15 one mole for each mole of trimethylamine which is
`the
`present. Any other desired method of mixing
`reactants may be employed.
`Preferably at least one mole of ethylene oxide is present
`for each mole of trimethylamine and, if desired, a
`20 stoichiometric excess of the ethylene oxide may be pres(cid:173)
`ent. At least two parts by weight of the alcohol for each
`part by weight of the trimethylamine are preferably
`present in the reaction mixture, with from two to three
`parts by weight of alcohol for each part by weight of
`If desired,
`25 trimethylamine being the preferred range.
`more than three parts by weight of alcohol for each part
`by weight of trimethylamine may be employed although
`there is ordinarily no particular advantage in doing so.
`Since both trimethylamine and ethylene oxide are
`30 normally gaseous, it is preferable to carry out the reaction
`of the trimethylamine with the ethylene oxide and the
`water in a closed vessel although, if desired, the re(cid:173)
`action can be carried out in an open vessel at atmospheric
`In a closed vessel the course of the reaction
`pressure.
`35 can more readily be followed since by carrying out the
`reaction at a suitable temperature there will normally be
`a slight pressure built up in the reaction vessel at the
`beginning of the reaction and as the reaction proceeds to
`completion the pressure within the vessel · drops to at-
`40 mospheric pressure provided stoichiometric equivalent
`amounts of trimethylamine and ethylene oxide are em(cid:173)
`ployed. Thus, for example, if the reaction is carried
`out at a temperature of from about 10° to 20° C. using
`the ratios of reactants and of alcohol specified above, a
`pressure of from about ten to fifteen pounds per square
`45 inch above atmospheric pressure will normally be present
`in the reaction vessel at the start of the reaction. Then
`as the reaction proceeds to completion, the pressure
`If desired, the
`drops to or near atmospheric pressure.
`reaction can be carried out at pressures higher or lower
`·
`than those referred to above. Likewise the temperatures
`employed can be higher or lower than those referred to
`above. Thus temperatures of from 0 O to 100 ° C. can
`suitably be employed along with whatever pressure is
`55 developed in the reaction vessel by the reactants at the
`temperature employed. However, it is preferred that
`temperatures not higher than about 40° C. be used since
`temperatures above about 40° C. may give rise to dis(cid:173)
`coloration of the choline solution with attendant decom-
`position.
`When the reaction is carried out at relatively low tem(cid:173)
`peratures, e. g. 10-20° C., the reaction of the ethylene
`oxide with the trimethylamine and the water will be com(cid:173)
`plete in about five or six hours. At higher temperatures
`the reaction will proceed more rapidly and higher tem(cid:173)
`peratures may be employed if it is desired to speed up the
`reaction.
`On completion of the reaction of the ethylene oxide
`with the trimethylamine and the water, the alcoholic solu(cid:173)
`tion of choline which is obtained is then admixed with
`the acid which is to be used in forming the desired salt of
`choline, preferably using an alcoholic solution of the acid.
`
`This invention relates to choline and more particularly
`to the production of choline salts.
`Choline is a: member of the vitamin B group and is
`generally considered to be necessary for normal nutrition.
`When used as a supplement in animal and poultry feeds,
`choline is usually employed in the form of its chloride
`salt. Choline chloride is not as satisfactory as desired
`for use, however, in pharmaceutical preparations because
`of its rather bitter taste and its strong tendency to absorb
`In fact, a number of choline salts are rather
`moisture.
`hygroscopic and because of this production of such salts
`in an anhydrous condition is made more difficult.
`It is the object of this invention to provide improved
`means for the production of anhydrous salts of choline.
`A further object of the invention is to provide im(cid:173)
`proved means for producing salts of choline which are
`highly suitable for pharmaceutical use.
`Other objects of the invention will in part be obvious
`and will in part appear hereinafter.
`The above and other objects of the invention are ac(cid:173)
`complished by first reacting trimethylamine with ethylene
`oxide and water in an aqueous alcohol solution containing
`one mole of water for each mole of trimethylamine, treat-
`ing the resulting reaction mixture with whatever acid is
`to be used for producing the choline salt, preferably using
`an alcoholic solution of the acid, cooling the reaction
`mixture to a relatively low temperature, and then sepa(cid:173)
`rating from the cooled reaction mixture the choline salt
`which crystallizes therefrom at the low temperature;
`Choline salts produced in this manner are anhydrous and
`In addition, the yields
`have a purity of 99% or better.
`of choline salts which are obtained in this manner are as
`liigh and in most cases higher than the yields of choline
`or choline salts obtained by prior art processes.
`The novel process of the invention can be used to pro(cid:173)
`duce any desired salt of choline, but it is particularly
`useful for the production of choline salts which are to be
`used for pharmaceutical purposes since the salts ob(cid:173)
`tained are of very high purity and are anhydrous. Thus
`the process of th_e invention is highly useful for the pro(cid:173)
`duction of choline dihydrogen citrate and choline tartrate
`both of which are very useful for incorporating choline
`into pharmaceutical .preparations. The process of the
`invention will therefore be described primarily with
`respect to the production of choline dihydrogen citrate
`and choline tartrate although it will be understood that
`the .process is also highly suitable for producing other 60
`salts of choline, e. g. choline chloride, whenever it is
`desired to produce those salts in a.high state of purity and
`_in anhydrous condition.
`The alcohols which are suitable for use in the process
`of the invention are aliphatic alcohols which are water- 65
`miscible and which contain from one to four carbon
`atoms. Thus methyl alcohol, ethyl alcohol, propyl al(cid:173)
`cohol, isopropyl alcohol, and tertiary butyl alcohol are
`all highly suitable for use in the process of the invention
`both in carrying out the reaction of the ethylene oxide
`with the trimethyl amine and the water and in reacting
`
`50
`
`70
`
`Apotex Exhibit 1020.001
`
`

`

`,
`
`3
`This reaction mixture is cooled to about 5° C. or below
`and held at that temperature for a short time, e. g. about
`two to three hours is sufficient although to insure recovery
`of all the desired salt it is preferred to maintain the low
`temperature for at least about six hours. The desired 5
`choline salt is then recovered in crystalline form from
`the cooled mixture by any desired means, e. g. filtration
`or centrifugation. The desired choline salt will be anhy(cid:173)
`drous, have a purity of 99% or better and the yields will
`normally run about as high or higher than any other 10
`method for preparing choline or its salts.
`In order to aid the crystallization of the choline salt, it
`is preferred that a relatively concentrated alcoho lie solu(cid:173)
`tion of the desired acid be employed in admixing the acid
`with the alcoholic solution of choline. Thus a saturated l 5
`alcoholic solution of the desired acid can be employed and,
`if desired, that solution may be prepared using an alcohol
`which has been heated to or near its reflux temperature in
`order. to give a higher concentration of the acid in the
`solvent. By using such a heated, saturated solution of the ZO
`acid, the total amount of solvent present when the choline
`salt is being crystallized will be less than if a more dilute
`solution of the acid is employed. A reduction in the
`amount of solvent will, of course, aid the crystallization
`of the choline salt. Any desired concentration of the al- 25
`coholic solution of the acid can be employed, however,
`since the concentration of the alcoholic solution of the
`choline salt can be adjusted to any desired concentration
`before carrying out the crystallization of the salt merely
`by evaporating any desired amount of solvent from the 30
`solution prior to carrying out the crystallization. The
`more dilute the solution of the choline salt is, the greater
`will be the time required for crystallization of the salt at
`any particular temperature. Another advantage of using
`a hot alcoholic solution of the acid in admixing the acid 35
`with the choline is the fact that the purity of the recovered
`choline salt appears to be greatest in most cases when the
`acid is admixed with the choline in that manner.
`For a fuller understanding of the nature and objects
`of the invention reference may be had to the following 40
`examples which are given merely as further illustrations
`of the invention and are not to be construed in a limiting
`sense.
`
`Example I
`153 gm. of trimethylamine were dissolved in 387 gm.
`of methyl alcohol to which 46 gm. of water had previously
`been added. The solution was cooled to about 0° C. and
`then 114 gm. of ethylene oxide gas were introduced into
`the solution. The reaction mixture was maintained at
`atmospheric pressure and a temperature of about 0° to
`10° C. overnight. A 64 gm. portion of this reaction mix(cid:173)
`ture containing free choline was added to a refluxing solu(cid:173)
`tion of 31.5 gm. of anhydrous tartaric acid in 100 ml. of
`methyl alcohol. This mixture was then cooled with agita- 55
`tion to 5° C. Crystallization of the choline tartrate took
`place quite rapidly at the low temperature. The crystal(cid:173)
`line choline tartrate was filtered from the cooled solution.
`The crystals were white in color, anhydrous and had a
`purity of 99%. The yield was 45.7 gm. which was a
`yield of 76.3% based upon the amount of trimethylamine
`employed. Another 64 gm. portion of the reaction mix(cid:173)
`ture containing free choline was added to a refluxing
`solution of 44.4 gm. of anhydrous citric acid in 275 ml. of
`isopropanol. This mixture was then cooled with agitation
`to 5° C. On cooling, an oil separated which crystallized 65
`into white crystals after agitating the cooled mixture for
`about an hour. The mixture was held overnight at about
`5° C. On filtering the cooled mixture, 59 gm. of white
`crystalline choline dihydrogen citrate having a purity of
`99% were obtained. Based upon the amount of tri(cid:173)
`methylamine employed, the yield was 82.8%.
`Example II
`30 lbs. of trimethylamine were added to 70.4 lbs. of
`methyl alcohol to which 9.2 lbs. of water had previously 75
`
`4
`been added. To the resulting solution in a closed vessel
`23 lbs. of ethylene oxide gas were introduced and the re(cid:173)
`sulting mixture then maintained at a temperature of 15 ' -
`20° C. and agitated for six hours. During the reaction
`fae pressure in the reaction vessel varied from about 12
`lbs.I sq. in. at the start of the reaction to zero lbs./sq. in.
`at the end of the reaction. The resulting solution was
`then added with agitation to a refluxing solution of meth(cid:173)
`anol containing 75 lbs. of tartaric acid dissolved therein.
`The mixture thus obtained was then cooled to 0° C. and
`held at that t•emperature overnight. The white crystalline
`choline tartrate which formed was separated from the
`solvent by filtration and air dried. 101 lbs. of anhydrous,
`crystalline choline tartrate having purity of 99.8% were
`obtained. This was a yield of 79% based on the amount
`of trimethylamine employed.
`Example III
`30 lbs. of trimethylamine were added to 70.4 lbs. of
`methyl alcohol to which 9.2 lbs. of water had previously
`been added. To the resulting solution in a closed vessel
`23 lbs. of ethylene oxide gas were introduced and the re(cid:173)
`sulting mixture then maintained at a temperature of 16 ° -
`30 ° C. and agitated for six hours. During the reaction the
`pressure in the reaction vessel varied from about 17.5
`lbs./sq. in. at the start of the reaction to zero lbs.I sq. in.
`at the end of the reaction. The resulting solution was
`then added with agitation to a refluxing solution of 40
`liters of isopropyl alcohol containing 95 lbs. of citric acid
`dissolved therein. This mixture was then cooled to 0° C.
`and held at that temperature overnight. The white crys-
`talline choline dihydrogen citrate which formed was sepa(cid:173)
`rated from the solvent mixture by filtration and dried in
`vacuo. 117 lbs. of anhydrous, crystalline choline dihydro(cid:173)
`gen citrate having a purity of 99.6% were obtaine~. This
`was a yield of 78% based on the amount of tnmethyl-
`amine employed.
`Having described our invention, what we claim as new
`and desire to secure by Letters Patent is:
`1. A process for preparing a crystalline anhyd_rous salt
`of choline having a purity of at least 99% which com(cid:173)
`prises the steps of ( 1) reacting at least one mol of ethyl(cid:173)
`ene oxide with one mo! of trimethylamine in an aqueous
`alcoholic solution containing one mol of water for each
`45 mol of said trimethylamine, the alcohol which is em(cid:173)
`ployed containing from 1 to 4 carbon ~toms a~d being
`water-miscible, (2) admixing the resultmg choline con(cid:173)
`tained in the reaction mixture with at least one mol of
`an acid for each mol of said choline thereby forming a
`50 salt of said choline, (3) crystallizing out of said reaction
`mL"ture said choline salt, and ( 4) recovering said crys(cid:173)
`talline anhydrous choline salt.
`2. The process of claim 1 in which said crystallization
`step is carried out between 0° and 5° C.
`3. The process of claim 2 in which said period of time
`is at least about 6 hours.
`4. The process of claim 1 in which the acid is dis(cid:173)
`solved in a water-miscible alcohol containing from one
`to four carbon atoms prior to admixing the acid with the
`DO choline-containing reaction mixture.
`5. The process of claim 4 in which the temperature
`of said alcoholic solution of the acid is approximately the
`reflux temperature of said solution when it is admixed
`with the choline-containing reaction mixture.
`6. The process of claim 5 wherein the acid is tartaric
`acid.
`7. The process of claim 5 wherein the acid is citric acid.
`8. A process for preparing crystalline anhydrous
`choline tartrate having a purity of at least 99% which
`70 comprises ( 1) reacting at least one mol of ethylene oxide
`with- one mol of trimethylamine in an aqueous methanol
`solution containing one mol of water for each mo! of
`said trimethylamine, (2) admixing the resulting reaction
`mixture with a refluxing methanol solution of tartaric
`acid, said solµtion containing at least one mol of tartaric
`
`Apotex Exhibit 1020.002
`
`

`

`P'
`
`s
`
`2,8'10,198
`
`acid for each mot of choline present in said reaction mix(cid:173)
`ture thereby forming choline tartrate, ( 3) crystallizing
`out of said reaction mixture said choline tartrate, and ( 4)
`recovering said anhydrous choline tartrate.
`9. A process for preparing crystalline anhydrous 6
`choline dihydrogen citrate having a purity of at least 99%
`which comprises ( 1) reacting at least one mol of ethyl(cid:173)
`ene oxide with one mol of trimethylamine in an aqueous
`methanol solution containing one mol of water for each
`mol of said trimethylamine, (2) admixing the reaction 10
`mixture with a refluxing isopropanol solution of citric
`acid containing at least one mol of citric acid for each
`mol of choline present in said reaction mixture thereby
`forming choline dihydrogen citrate, ( 3) crystallizing out
`of said reaction mixture said choline dihydrogen citrate,
`and ( 4) recovering said anhydrous choline dihydrogen
`citrate.
`
`6
`References Cited in the file of this patent
`UNITED STATES PATENTS
`Roeder ---------------- Apr. 11, 1939
`Komer ---------------- Mar. 18, 1952
`Klein et al. _____________ Dec. 30, 1952
`
`2,153,591
`2,589,707
`2,623,901
`
`8,031
`
`FOREIGN PATENTS
`Great Britain ------------------- 1914
`
`OTHER REFERENCES
`Meyer et al.: Ber., 54, 2279 (1921).
`Nakada: Chem. Abstracts, vol. 48, p.12793 (1954).
`Conant et al.: The Chemistry of Organic Compounds,
`15 p. 194 (1954).
`
`Apotex Exhibit 1020.003
`
`