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2,462,782
Patented Feb. 22, 1949
UNITED STATEg ZRATENT ()FFICE
2,462,782‘
PRODUCTION OF TOTAQUINE
Jacob B. Shohan, West Orange, N. 1., assignor
to American Home Products Corporation, New
York, N. Y., a corporation of Delaware
1
No Drawing. Application June 6, 1945,
Serial No. 597,969
7 Claims. (Cl. 260-284)
This invention relates to a method of recover
parison with the alkali method that the acid ex~
ing totaquine from plant material containing cin
traction step removes from the vegetable raw ma
chona alkaloids, such as cinchona bark, in which
desired alkaloids are extracted from the plant
material by aqueous mineral acids, and impurities
are then precipitated from the acid extract by
terial relatively large amounts of inorganic im
purities and of colored, gummy organic impuri
ties which are not extracted by alkali, or, if ex
tracted, are not taken up by the solvent. Ac
partial neutralization to a controlled acidity with
out substantial precipitation of the desired alka
loids. More particularly, this invention relates
cordingly, the raw alkaloids recovered by the
alkali-solvent method are easy to purify to meet
pharmaceutical requirements, while the acid-ex
to such a process in which part of the impuri 10 tracted cinchona alkaloids are more difficult to
ties are precipitated and separated from the acid
purify by any method which is at the same time
extract by partial neutralization to a controlled
cheap, simple and effective. By “inorganic im
acidity, the alkaloids are then precipitated from
purities” I mean to include all such contaminants
the partially puri?ed extract by alkali, and re
as leave an ash on ignition, although from the
maining impurities are separated from the alka 15 point of View of pure chemistry some or all of
loids by ?ltration after resolution of the alkan
them may be salts of organic acids or other metal
loids in an aqueous medium of a controlled pH
organic compounds.
value at which remaining impurities are undis
It is one object of this invention to provide a
solved. An additional and optional feature of
cheap and e?ective method for recovering cin
my invention is the adsorption of impurities from 20 chona alkaloids.
an acid extract of totaquine to an inorganic pre
It is another object of this invention to provide
cipitate, such as calcium phosphate, formed in
a method of this sort which obviates the use of
situ.
organic solvents.
The cinchona alkaloids are customarily recov
It is another object of this invention to provide
ered from plant material such as cinchona bark 25 a method of this sort which is particularly adapted
by digestion of the ?nely divided material with
to recover totaquine.
an aqueous alkaline medium in the presence of
It is a further object of this invention to pro
an organic solvent. The alkaline medium is usu
vide cheap and e?ective methods of purifying
ally milk of lime with some added sodium hy
acid-extracted cinchona alkaloids.
droxide, and the solvent is usually a water-im
Another object of my invention is to provide a
miscible hydrocarbon such as aIight petroleum
method of extracting cinchona alkaloids which
naphtha, benzene or the like. The alkali sets
may be carried out in the ?eld with simple equip
free the alkaloid bases which are taken up by the
ment.
solvent. The solvent layer is separated, and the
Other objects and advantages will be apparent
alkaloids are recovered from the solvent in the 35 to those skilled in the art, from the following de
form of salts by extraction of the solvent with
scription.
aqueous mineral acid, usually sulfuric acid.
According to my invention 1 extract cinchona
The acid extract may then be worked up for re
alkaloid-containing vegetable material, such as
covery of individual alkaloid salts, e. g. the sul
cinchona. bark, with dilute aqueous mineral acid.
fates respectively of quinine and cinchonine, or 40 The bark is preferably ground or otherwise com
the total alkaloid mixture may be recovered in
minuted before extraction. Sulfuric acid is the
the form of mixed salts or bases for therapeutic
preferred extracting agent, but other acids, such
use as totaquine.
as hydrochloric and phosphoric acids, can be
Instead of the above-described alkali~solvent
used. It is advantageous to vcarry out the ex
extraction. the direct extraction of cinchona al 45 traction in a countercurrent stepwise manner'so
kaloids from plant material with dilute acids has
that fresh acid is used to extract nearly ex
been proposed and to some extent used commer
hausted bark and acid nearly saturated with
cially. It has the great advantage over the alkali
alkaloid is brought into contact with unextracted
method that the use of organic solvent is either
bark. This utilizes the acid ef?ciently and re
eliminated or minimized, thus reducing processing 50 duces the amount of alkali needed in subsequent
cost and eliminating or minimizing the sub
steps. The acid extractant may be heated dur
stantial ?re and health hazards involved in using
ing extraction, but heating is not necessary.
organic solvents.
The acid extract thus prepared, contains the
The acid extraction method, however, has so
desired alkaloid salts in solution and also con
far suffered from the great drawback in com 56 tains in true and colloidal solution and in sus
2,462,782
.
3
are precipitated by alkali in the usual way from
the ?ltrate, washed with water, and dried. A
good grade of commercial totaquine is thus ob
ties. The color of the solution may be dark bro‘ 1
to yellow, and the reaction is distinctly acid.
about pH 4 or less. I have discovered that
‘l
a solution is cautiously neutralized to a pH not
a
above
sodium
about
carbonate
7 by the solution,
addition of
a point
alkali may be
reached at which all, or the major part of, the
impurities are precipitated as a dark violet sti
4
After ?ltration of the hot solution, the alkaloids
pension considerable amounts of inorganic inr
purities and of colored, gummy organic impu
tained.
'
.
As stated above, the initial extraction of the
bark may be carried out hot or cold, but cold
extraction is satisfactory and is usually more
convenient to carry out in the .?eld since con
10 ~slderalole volumes of liquid are involved. Sub
solid. The dissolved impurities aididetermn
ing the end point of this neutralization since they
include a natural indicator which turns from
sequent resolutions and ?ltrations in the puri
?cation of crude totaquine are preferably carried
out» at or near the boiling temperature; the vol
umes ofliquid involved being smaller, this offers
brownish yellow to violet at about pH '7.
no great di?iculty in ?eld work.v
.
15
The precipitate is removed. from‘the extract by
In view- of the quantitative and qualitative
?ltration, centrifuging or decanting, andtis' dis~
variations in the composition of commercial
carded after washing. If the neutralization; is
cinchona barks and the impracticability of close
carefully carried out, the washed precipitate. con
control of all the conditions in actual operations,
tains little or no alkaloid. The lower‘the p'l-l at
it is not possible to de?ne precisely the optimum
which the precipitation is effected, the less risk 20
pHfor each step. 'Tests in a small scale must
there is of losing alkaloids in the precipitate, but
be run from time to time. ' However, with the
the less effective also is'the removal of impurities
aid of such tests the operator will readily recog
from solution.
‘
nize
the proper end pointswithin the pH ranges
' The ?ltrate is made alkaline, e. g. with sodium
carbonate solution, and brought'to a-pH- of ap 25 herein set forth.
An unexpected feature of the above described
, proximately 8. This causesthe'precipitationof
work was that by working with these cinchona
substantially all the alkaloids present in the so~
alkaloid-containing materials and manipulating
lution in the form of'their insoluble bases. vThe
them alternately from acidic to basic and basic
product thus obtained has ‘been freed ‘of the
maiorvpart of‘ the impurities originally present,‘ 30 to acidic reactions in a narrowrange of pH value,
but usually stillhas' too high‘ an ash content to
meet U. S. P. speci?cations. After’ washing, the
precipitate consists‘ of a‘ wet-heavy mass which
may'contain in the'neighborhood of ZO'percent
solids. It is treated with 501: percent sulfuric
acid, and hot Water is added; "the' “pH‘is then
cautiously adjustedby the addition‘of sodium
carbonate solution to a’ value between 6 and '7
that is approximately from just below pH 7 to
about pl-I 8, it was‘ possible with intermediate
?ltration to effect suf?ciently- complete'separa
tion of impurities from the alkaloids so that'the
alkaloids met U: S. P. totaquine requirements,
while doing this, to recover a satisfactory
percentage of the alkaloids present in the bark.
It will thus be seen that my invention furnishes
a simple, economical and effective method,
at which substantially all‘of the desired alkaloids
adapted for use in the ?eld, of recovering ‘cin
40
.are again brought into solution" in the form" of
chona alkaloids from vegetable materials con—
vsalts, while. a residue. ofdif?cultly soluble salts
taining such alkaloids without the use of organic
and some coloring matter" remains undissolved.
solvents and without the necessity of using com
.The residue is separated from the"'solution""by
plicated or bulky equipment.
‘?ltration or otherwise and: a‘ ?ltrate is obtained
Speci?c examples 'of the application of my in
containing the‘ desired alkaloids ‘in solution as
vention follow.
'
salts. They can then be directlyv precipitated‘ by
Example 1
the. addition of alkali; and recovered *by "?ltration:
' or by a'slight shift. of the ‘acidity towards the
pounds of pulverized cinchona --bark is
alkaline side, near to but never above about pH
stirred into approximately45 pounds of 10. per
‘ ‘7,. a small additional amount‘ of ‘oily .or sticky
cent sulfuric acid; after complete wetting. of. the
'material can sometimes be precipitated and re
bark the mixture'is allowed tosteep for 2 to 6
moved by ?ltration before the’?nal precipitation
hours, or, if convenient, over night. Appproxi
of the totaquine.
‘mately 1/2 to 2/3 of the liquid is then withdrawn
"Instead of sodium carbonate,‘ other alkaline
from the slurry by ?ltration, and an equivalent
materials maybe used in the above'edescri'bed
' amount of water added to the wet residue. The
precipitations—e. g., potassium carbonatepso
?rst extract, its ‘acid contentihaving been re
' dium-hydroxide," potassium ‘hydroxide, ammonia
duced to about 8%, is then used for wetting out
'or’the like.
'
‘
and extracting an additional amount of pulver
Totaquine so produced will vary ‘in color from
ized bark equal to that ?rst used. In order to
buff to gray, and ‘be sufficiently lowin ash to
make» a tractable slurry, wash water from the
meet U. S. P. ‘requirements.
?rst batch is added to this second batch, further
‘If a specially purezgrade ‘of 'totaquine is‘de
bringing down the concentration of acid and
sired, it‘ maybe ‘obtained in the ‘following way.
making up the weight of ?rst extract and wash
“Partially'puri?ed"totaquine precipitated from
‘I ingsgto about 45 pounds. The'extract and'wash
acid ‘extract 'by one of-‘thamethods' described
ings from the second batch ‘are used to extract
.above is heated in‘ ‘dilute phosphoricv 'acid"solu
additional bark. Extractions are continued in
"tion to give a turbid solution "in-‘which a‘ brown
this way in series until the acid initially present
'?occulent precipitate is‘suspended. 'A thin sus
is gradually reduced to a pH of about 4. Succes
pension-of calcium hydroxide is added to ‘bring
sive batches of bark are-advanced through this
' the pH of'the solution to about 7. ' A_ precipitate
series of extractions ‘in such a way-‘that fresh
"of calcium phosphate is‘thus formed‘ which not
unextracted bark is treated with nearlys'aturated
only " carries ' down ‘ > the ’ flocculent' suspended
‘matter and ‘aids * in its ‘?ltration-,1 but "to "which a
" substantial amount of the'dissolved impurities
~are'adsorbedwhen the'pH-isbrought to about '7.
acid extract, the bark entering and-the'acid-ex
tract leaving the series at this step; and‘ nearly
*exhaustedbark is'contacted with-fresh '10 per
5
2,462,782
cent acid, the bark leaving and the acid entering
totaquine light tan in color and containing only
the extraction at this step. Water may be added
where necessary to maintain a ratio of about 45
pounds of liquid to 10 pounds of bark.
1 percent ash.
-
The nearly saturated dilute sulfuric acid ex~
I claim:
1. In a process for recovering puri?ed cinchona
alkaloids by acid extraction of vegetable mate
tract produced by this series of extractions and
rial containing such alkaloids, the steps which
having a pH of approximately 4 is a brown to
comprise: partially neutralizing an acid solution
of cinchona alkaloids containing also acid-ex
tractable impurities by adding sui?cient alkali to
Sodium carbonate solution of 15 percent is then 10 selectively precipitate at least a portion of said
slowly added with stirring to the acid extract until
impurities but insuf?cient to precipitate a major
the pH is brought to a point, approximately 7, at
amount of the alkaloids present, removing the
which a change in color of the liquid from brown
precipitated impurities from the mother liquor,
ish yellow to violet occurs, and precipitation of
and thereafter recovering alkaloids from the
a dark violet sticky solid occurs without 15 mother liquor,
substantial precipitation of alkaloids.
The
2. In a process for recovering puri?ed cinchona
sticky solid precipitate is ?ltered oiT on a suc~
alkaloids by acid extraction of vegetable material
tion ?lter and washed with water to free it of
containing such alkaloids, the steps which com~
mother liquor. The precipitate is then discarded.
prise: adding to a mineral-acid solution of cin
The combined ?ltrate and washings are then
chona alkaloids containing also acid-extractable
brought to a pH of 8 by the addition with stirring
impurities an alkaline material in amount to re
of a further amount of 15 percent sodium car
duce the acidity of the solution to about pH '7,
bonate. The precipitate so produced contains
thereby selectively precipitating a major portion
substantially all of the desired alkaloids freed
of the dissolved impurities without substantial
from the major part of the contaminating im 25 precipitation of the desired alkaloids, separating
purities originally present. This precipitate is a
the resultant precipitate from the mother liquor,
wet dark-gray colored mass containing in the
thereafter adding additional alkaline material to
neighborhood of 20 percent solids. The solids
the mother liquor in amount sufficient to bring its
brownish yellow solution. Its "pl-I is determined
by “Hydrion” (Universal) test paper.
have an ash content too high to meet U. S. P.
alkalinity to at least pH 8, thereby precipitating
requirements. This wet mass is slurrie‘d with 30 desired alkaloids in at least partially puri?ed
form, and recovering the precipitated alkaloids.
su?icient hot water to make a thick suspension,
3. In a process for recovering puri?ed cinchona
and a small amount of 50% sulfuric acid is adder
alkaloids by acid extraction of vegetable mate
with agitation, the amount being controlled to
rial containing such alkaloids, the steps which
lower the pH of the liquid to just below 7 as deter—
comprise: adding to a mineral-acid solution of
mined by “Hydrion” (Universal) test paper. This
brings substantially all the desired alkaloids into
cinchona alkaloids containing also acid-extrac
solution but leaves undissolved di?iculty soluble
table impurities an alkaline material in amount
to reduce the acidity of the solution to about
salts and a small amount of colored material.
pH '7, thereby selectively precipitating a major
This mixture is ?ltered hot; the ?ltrate is boiled
portion of the dissolved impurities without sub
with decolorizing carbon (7-10 grams “Darco”
stantial precipitation of the desired alkaloids,
No. 60 per liter), and again ?ltered. A ?lter aid
separating the resultant precipitate from the
(“Filter-eel,” 10-15 grams per liter) is advan
mother liquor, thereafter adding additional alka
tageously added prior to one or both of these ?l
trations. The ?nal ?ltrate is a clear light yel 45 line material to the mother liquor in amount suf
?cient to bring its alkalinity to at least pH 8,
low solution. It is cooled and totaquine is pre
thereby precipitating desired alkaloids, reslurry
cipitated from the ?ltrate by the addition
ing the precipitate with water to form a tractable
of 15% sodium carbonate to a pH of about
slurry, adding mineral acid to the slurry in con
8. After standing an hour, the precipitate is
trolled amount to bring the acidity of the slurry
?ltered, washed and dried. The cream colored
to about pH '2, thereby selectively dissolving the
product is of good commercial purity, and has an
desired alkaloids, separating undissolved impuri
ash content of about 1.2 %—Well below U. S. P.
ties from the solution, and thereafter recovering
requirements.
alkaloids from the solution.
Example 2
4. In a process for recovering puri?ed cinchona
alkaloids by acid extraction of vegetable material
A totaquine precipitate partially puri?ed by
containing such alkaloids, the steps which com
fractional precipitation from an acid extract as
prise: partially neutralizing an acid solution of
described in Example 1 and having a solids con
cinchona alkaloids containing also acid-extrac
tent of about 50 percent is heated with approxi
table impurities by adding sufficient alkali to
mately six times its weight of 6 percent phosphoric
selectively precipitate at least a portion of said
acid. The resultant solution is turbid, and a
impurities but insu?icient to precipitate a major
brown flocculent precipitate remains in sus
pension.
A thin suspension of calcium hydroxide is added
to the mixture in amount sui?cient to bring the
pH up to approximately 7 as determined by “Hy
drion” (Universal) test paper.
‘This causes a
heavy precipitation of calcium phosphate in the
solution, to which is absorbed a substantial
amount of the remaining impurities present. On
?ltration without the addition of activated car
bon, a clear yellow solution is obtained. This is
further neutralized with sodium carbonate, the
precipitated alkaloids ?ltered o?, washed with
water, and dried. The resultant material is a 75
portion of the alkaloids present, removing the
precipitated impurities from the mother liquor,
then adding su?icient alkali to the mother liquor
to precipitate partially puri?ed alkaloids, separat
ing the precipitated alkaloids from the second
mother liquor so formed, redissolving the precipi
tated alkaloids in dilute phosphoric acid, adding
calcium hydroxide to the resultant acid solution
to a pH not above 7 to form a precipitate of
calcium phosphate and adsorbed impurities,
separating the precipitate from the third mother
liquor so formed, and recovering puri?ed alkaloids
from this mother liquor.
5. The method of recovering totaquine, which
:1 851462, 782
7
--':comprisesi~extracting ‘plant material containing
i the alkaloids while leavingfat "least ' a part .of-ethe
cinchona alkaloids with an aqueous mineral acid,
precipitating acid-extracted impurities by partial
~_:neut-ralization to a'pHV-not above 7,- removing the
impurities ~ ~ undissolv'ed,» separating 1 . the ,-=undis
I’ solved impurities, and . recovering» totaquine ~ from
the resultant solution.
.
'7. The method de?ned in claim 6; in which vpar
separated. impurities; and-recovering totaquine .‘ CK
tially extracted plant material is- furthers-ex
tracted with fresh dilute sulfuric acid andnmex
ii 6.2 The method of recovering 'totaquine; ‘which
‘from , the resultant’ solution.
comprises extracting plant" material containing
.ytracted plant material is extracted» with’, dilute '
.calkalizto the~resultantysolution to a' pI-I‘of about
8 thereby forming a precipitate 'consistingof a
"major fraction‘ of: alkaloids :and a‘ minor‘ fraction
The following ‘references ‘are of record ini'the
file of this patent:
UNITED. STATES, PATENTS
sulfuric acid partially‘ saturated :with- cinchona
cinchona alkaloids withz-‘dilute- aqueous sulfuric
i
zlacidgadding toxthelac'id extract sufficient alkali to. ll) alkaloids.
"selectively precipitate »- acid-extracted eirnpurities
REFERENCES‘,
.jJACOB
CITED
B. 'SHOI-IAN.
:butinsu?icient to raise Ithe'pH above '7, remov
ing the precipitatedr-impurities, adding a soluble
r'ofrresidual acid-extractable impurities, separat
ing the ‘precipitate, redissolving the ‘precipitate
fin a*limited amotmt-ofdilute sulfuric acid suffi
':-.cient; to 1' selectively 1- dissolve " substantially all of 20
Number
378,233
- Name
' lDate
Casamaj or _______ _: Feb. 21; :1888
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