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Патент USA US2407561

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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
-
‘
'
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