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Патент USA US2390499

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’ Patented Dec. 11, 1945
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
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
These previous or older methods em
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
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
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
pantothenate. I Similarly,
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
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
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
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