Date: Fri, 7 Nov 1997 01:57:35 EST
From: Chris Jenks <email@example.com>
To: Multiple recipients of list <firstname.lastname@example.org>
Subject: Ibogaine from Voacangine
For those of you who live around Voacanga africana trees, the following
patent should be of interest. It insists that it is more practical to
obtain ibogaine from these trees by converting the voacangine therein into
ibogaine in a simple chemical process. The extra complexity of this
approach is more than compensated for by the relative abundance of V.
africana and of voacangine in the tree. The patent also describes a simple
one-step conversion of voacangine to noribogaine, the metabolite of
ibogaine suspected of causing ibogaine's long term effects. The ibogaine
produced from voacangine is identical to that from T. iboga in every way
tested, including optical rotation. In a previous discussion on this list
there was some doubt about the optical purity of ibogaine made from
voacangine, and this patent seems to settle it.
Janot, Maurice-Marie and Goutarel, Robert. "Derivatves of the ibogaine
alkaloids.", Unites States patent, (November 19, 1957), 2,813,873.
This invention relates to a method of obtaining alkaloids and more
particularly it relates to a method of obtaining new alkaloids of the
general formula shown below:
[Here is an incorrect structure for noribogaine, called O-demethyl-ibogaine
in this patent. The correct structure of ibogaine hadn't been determined
yet. R1 is on the oxygen, designated as position 5, and R is on the carbon
attached to nitrogen which bears no other hydrogen.]
in which R = H, R1 = H or p-toluene-sulfonyl, starting from voacangine, of
the general formula cited above wherein R = -CO2CH3, R1 = CH3.
It is an object of this invention to provide a relatively simple but
effective method of producing alkaloids which are useful in industry and in
the veterinary and medical arts.
It is a further object of this invention to provide a novel method of
obtaining alkaloids from ibogaine, wherein the methyl group of methoxyl in
the 5 position of the indole radical has been replaced by hydrogen or by a
p-toluene sulfonyl radical, and to a new alkaloid product therefrom.
Another object of the present invention is to provide a method of
changing voacangine to ibogaine and of changing alkaloids of iboga to
As the above formula clearly indicates, all alkaloids made according to
the present invention are derived from ibogaine C20H24-26N2O, in which R =
H, R1 = -CH3, and wherein the methyl group of methoxy at the 5-position of
the indole radical has been replaced by hydrogen or by a p-toluene sulfonyl
While it would appear logical to produce the new derivatives of the
invention from ibogaine, the applicants have found that it is much more
advantageous and desirable to prepare these derivatives by starting with
voacangine as a source. It has been found that voacangine is extracted from
the bark of the voacanga tree plant. The voacanga africana, stapf, is able
to supply up to 5 grs. per kilo, whereas ibogaine is found in the roots of
tabernanthe iboga (H.Bn) at a concentration of 3 grs. per kilo. It is both
apparent and obvious that gathering the bark is much easier than gathering
the roots, and that the former procedure does not bring about the
destruction of the plants. It should also be noted that the voacanga is
much more widely prevalent than the iboga.
The process to which this invention relates consists in heating
voacangine in alkaline solution in a suitable solvent to a temperature
which is preferably close to boiling. It is possible, for instance, to
operate on refluxing with methanol potassium. The saponified product is
isolated and treated with an acid medium at a temperature between 35 and 55
degrees C., but which is preferably close to 40 degrees C. This treatment
causes decarboxylation, and ibogaine hydrochloride is isolated which is
transformed into the base ibogaine by methods known per se such as by
adding an alkaline solution. Said base ibogaine is then treated by
refluxing with a hydrobromic acid solution in acetic acid with a view to
demethylating it. After the usual washings, O-demethyl ibogaine is isolated
in the form of its hydrochloride, which is isolated, transformed into a
base by conventional methods and treated with p-toluene sulfonyl chloride
in order to obtain the corresponding p-toluene sulfonate.
It is to be noted that the conversion of voacangine to ibogaine, which
has not been described in the past and is very advantageous for the
preparation of the alkaloid of iboga, also forms part of the present
It is also possible according to the present invention directly to treat
voacangine by refluxing a hydrobromic acid solution of the same in acetic
acid and thus directly to isolate O-demethyl ibogaine without being obliged
to isolate the intermediate ibogaine.
With the above general features in view, the following examples will
serve to illustrate the invention without however restricting the scope of
the invention. It is notably possible to change the nature of the solvents,
to vary the conditions of temperature, the time of reaction or the order in
which the reagents are introduced into the reaction medium, to replace the
alkaline or basic agents used by other equivalent ones without thereby
exceeding the scope of the invention.
Example 1. - The conversion of voacangine [see Formula I, wherein R =
-CO2CH3, R1 = -CH3] into O-demethyl-ibogaine hydrochloride [see Formula I,
wherein R = H, R1 = H]
1 gr. of voacangine extracted from voacanga africana stapf and voacanga
thouarsii R. and Sch. vr. obtusa (K. Sch.) Pichon (cf. M. M. Janot and R.
Goutarel, C. R. 240, 1800 (1955)) is heated to boiling under nitrogen and
in a mixture consisting of 20 cm.3 of crystallizable, glacial, acetic acid
and 5 cm.3 of 48% hydrobromic acid. Heating of the mixture is continued for
four hours, after which the resultant solution is vacuum evaporated until
dry, and the residue is taken up with 200 cm.3 of lukewarm water. The
aqueous solution is alkalized with ammonia or any other alkali such as mild
NaOH or KOH and extracted three times with 50 cm.3 of ether. The ethereal
solution us washed with water, evaporated until dry, and the residue is
taken up with 5 cm.3 of methanol or other alcohol such as ethanol, or
propanol. The methanol solution is acidified to pH 3 with hydrochloric acid
and slowly added to an equal volume of ether. The hydrochloride of
O-demethyl-ibogaine is separated in the form of needles which are
recrystallized in a 1:1 methanol-ether mixture, then in pure methanol.
The product takes the form of small colorless needles, soluble in water,
ethanol and methanol, insoluble in ether and petroleum ether. The crystals
melt at 310-312 degrees C. in a capillary tube and have the following
characteristic ultraviolet absorption bands:
In alcohol solution: gamma = 278 nanometers; log epsilon = 3.88
In 0.01 N alcohol potassium: gamma = 285 nanometers; log epsilon = 3.86.
The displacement of the maximum in an alkaline medium confirms the
phenolic nature of O-demethyl-ibogaine. The yield of the above operation is
The chemical analysis shows the following empirical formula:
As calculated ________ C, 68.6%; H, 7.6%; N, 8.4%
As found ___________ C, 68.7%; H, 7.6%; N, 8.5%
This is a new product.
Example 2. - Conversion of voacangine [see Formula I, wherein R = -CO2CH3,
R1 = -CH3] into ibogaine [see Formula I, wherein R = H, R1 = -CH3]
500 mg. of voacangine obtained from any suitable source are treated while
boiling for six hours in a solution of 4 grs. of potassium in 30 cm.3 of
methanol. The solution is vacuum evaporated until dry, then is taken up
with 30 cm.3 of water, the aqueous solution is then washed with 20 cm.3 of
ether and is acidified to pH 2 with hydrochloric acid. The solution is
vacuum evaporated until dry at a temperature of about 40 - 50 degrees C.,
and the residue is taken up four times with 100 cm.3 of a (4:1)
chloroform-methanol mixture. The potassium chloride is separated by
filtration, and the filtrate is vacuum evaporated until dry.
This method above produces 430 mg. of ibogaine hydrochloride which is
dissolved in 20 cm.3 of water and re-extracted three times with 10 cm.3 of
ether after having alkalized the aqueous solution with sodium bicarbonate,
potassium bicarbonate or ammonium bicarbonate or a carbonate thereof. The
ethereal solution obtained in this manner is vacuum evaporated until dry,
and the residue having been recrystallized in 5 volumes of ethanol produces
350 mg. of pure ibogaine. The characteristics of this compound are: M. P. =
150-151 degrees C. by capillary tube test, [alpha]D20 = -50+/-2 (c. = 1%
ethanol). The product obtained in this manner is in every respect identical
with a genuine sample of the naturally extracted ibogaine. The test of the
mixture produces no depression of the melting point and the values in the
ultraviolet and infrared spectrum agree.
Example 3. - Conversion of ibogaine into O-demethyl-ibogaine hydrochloride
[See Formula I wherein R = H, R1 = H]
1 gr. of ibogaine prepared according to the preceding example is treated
while boiling under nitrogen in a mixture of 20 cm.3 of acetic acid and 5
cm.3 of 48% hydrobromic acid for four hours. The solution is vacuum
evaporated until dry, and the residue is taken up with 200 cm.3 of lukewarm
water. The aqueous solution is alkalized with ammonia or some similar
alkali as herein indicated, and extracted three times, with 50 cm.3 of
ether. The ethereal solution obtained in this manner is treated as
indicated in Example 1, thereby producing O-demethyl-ibogaine: M. P. =
310-312 degrees C. by capillary tube test.
The product is in every respect identical with the O-demethyl ibogaine
described in Example I. The test of the mixtures produces no depression of
the melting point and the values of the spectra are in agreement. The yield
from the above conversion is above 95%.
Example 4. - Passing of O-demethyl-ibogaine hydrochloride to base
1 gr. of O-demethyl-ibogaine [hydrochloride] obtained according to the
preceding example is dissolved in 100 cm.3 of water, the solution is then
cooled to about 5-15 degrees C. and ammonia or other similar basic
substance is added drop by drop while stirring until precipitation is
completed. The solution is then separated preferably by centrifugation,
washed with water and then vacuum dried thereby producing base
O-demethyl-ibogaine with a quantitative yield.
This is a new product which is amorphous, soluble in ethanol and
methanol, insoluble in water. Its amphoteric phenolic nature makes it
soluble in acid aqueous solutions such as hydrochloric, nitric, sulfuric,
phosphoric, boric acid or strong basic solutions such as of KOH, NaOH, LiOH.
Example 5. - Preparation of O-p-toluene sulfonate of O-demethyl-ibogaine
[see Formula I wherein R = H, R1 = CH3-C6H4-SO2-]
1 gr. of base O-demethyl-ibogaine prepared according to Example 4
hereinabove is dissolved in 20 cm.3 of anhydrous pyridine, 3 grs. of
para-toluene sulfonyl chloride are then added, and the resultant solution
is allowed to stand for 2 days at room temperature. The resulting solution
is diluted with 200 cm.3 of water and is extracted three times with 50 cm.3
of ether. The ethereal solution is then washed with water, dried over
sodium sulfate or similar dehydrating agent and vacuum evaporated until
dry. There are produced 1.35 grs. of crude para-toluene sulfonate which are
dissolved in 50 cm.3 of benzene or toluene or xylol and chromatographed
over 35 grs. of neutral alumina. The benzene washings or eluate, after
having been evaporated until dry, is treated with hydrochloric methanol and
then crystallized in acetone.
There is produced the hydrochloride of O-demethyl-ibogaine O-para-toluene
sulfonate having an M. P. = 214-215 degrees C. according to capillary tube
technique. The product takes the form of small colorless needles, soluble
in water, ethanol and methanol, insoluble in ether and petroleum ether,
which have the following maximum ultraviolet absorption:
gamma = 285 nanometers; log epsilon = 3.87
The analysis of this product shows the empirical formula of
As calculated ________ C, 64.1%; H, 6.4%; N, 5.7%
As found ___________ C, 63.8%; H, 6.6%; N, 5.7%
The products or new alkaloids made according to the present invention are
valuable in the medical and veterinary art for medical and therapeutic
purposes, and in industry as intermediates for the development of finished
The new products of the present invention are characterized by their
excellent and effective cardio-tonic and general tonic properties and which
are combined with a remarkably low toxicity on the human being and other
animals. Also they can be used as intermediate products in the preparation
of other compounds of an alkaloidal nature.
In the description and examples it is to be noted that where a basic
material as ammonia is mentioned such term includes the bases such as NaOH,
KOH, and the like.
As to solvents, there are included methanol, ethanol, and propanol.
Ethereal solutions may be ether, chloroform, acetone and the like.
Throughout the specification it is to be noted that the term "demethyl"
is to be construed as meaning demethylated, i. e., wherein the methyl
radical is removed from the molecule of the compound.
While preferred methods of the invention have been described, it is to be
understood that various modifications may be made as to steps of procedure
and use of agents, materials, diluents, solvents, extractives, without
departing from the spirit and scope of the invention.
1. The method of producing new alkaloids of the general formula I:
[This picture is identical to the one at the beginning of the patent.]
wherein R = H, R1 = H or p-toluene sulfonyl, comprising heating voacangine
in an alkaline solution in a solvent selected from the group consisting of
methanol, ethanol, and propanol at a temperature which is preferably close
to boiling, isolating the resultant saponified product, then treating in an
acid medium at a temperature between 35-55 degrees C. forming ibogaine
hydrochloride, then isolating said ibogaine hydrochloride, then converting
into base ibogaine, treating said base by refluxing with a hydrobromic acid
solution in acetic acid so as to obtain O-demethyl-ibogaine hydrochloride,
then isolating the latter product and then converting into a base by
conventional methods, then treating with p-toluene-sulfonyl chloride so as
to produce the corresponding p-toluene sulfonate.
2. The method according to claim 1 wherein the voacangine is directly
treated by refluxing with a hydrobromic acid solution in acetic acid so as
to obtain, after the usual washings, O-demethyl-ibogaine hydrochloride,
then isolating and converting into a base and treating with p-toluene
sulfonyl chloride so as to produce the corresponding p-toluene-sulfonate,
the intermediate ibogaine not being isolated.
3. The process according to claim 1 wherein the saponification of
voacangine is carried out with methanol potassium.
4. The process according to claim 1 wherein the saponified product is
decarboxylated by heating to between 35-55 degrees C. in N hydrochloric acid.
5. The method of producing ibogaine which consists in heating a substance
containing voacangine in a lower alcohol alkaline solution at a temperature
approximating boiling, then heating with an acid medium at a temperature
between 35-55 degrees C., then converting the resultant ibogaine
hydrochloride into a base ibogaine, refluxing the last named product with a
hydrohalogen acid in the presence of an acid to demethylate said product,
washing to isolate O-demethyl ibogaine hydrochloride, alkalinizing said
last product then treating with p-toluene sulfonate.
6. As a new product, O-demethyl-ibogaine hydrochloride.
7. As a new product, O-demethyl-ibogaine.
8. As a new product, O-p-toluene sulfonate hydrochloride of
9. As a new product, O-p-toluene-sulfonate of O-demethyl-ibogaine.
No references cited.