Date: Fri, 7 Nov 1997 21:04:12 EST
From: Chris Jenks <firstname.lastname@example.org>
To: Multiple recipients of list <email@example.com>
Subject: Dickel's Extraction
The following paper is the best extraction of ibogaine I have found in
the literature. At one point there was about a kilogram of ibogaine sitting
in a lab at CIBA. I wonder what happened to all of it?
Dickel, D. F.; Holden, C. L.; Maxfield, R. C.; Paszek, L. E. and Taylor, W.
I. "The alkaloids of Tabernanthe iboga. Part III. Isolation studies.",
Journal of the American Chemical Society, (1958), 80, 123-125.
[Contribution from the Research Department, CIBA Pharmaceutical Products,
The alkaloids of Tabernanthe iboga. Part III.(1) Isolation Studies.
By D. F. Dickel, C. L. Holden, R. C. Maxfield, L. E. Paszek and W. I. Taylor
Received August 5, 1957
The present investigation of Tabernanthe iboga root records the isolation
of twelve compounds, which includes not only the four known alkaloids
ibogamine, ibogaine, tabernanthine and iboluteine but also iboquine,
desmethoxyiboluteine, the hydroxyindolenine derivatives of ibogaine and
ibogamine, voacangine, gabonine, kisantine and kimvuline. Of these, the
latter three have not been described previously.
The current interest in Tabernanthe iboga initiated a more detailed
investigation of the alkaloidal content of the root. Emphasis was placed
both on the preparation of the major alkaloids in a state of high purity
and on the isolation of the greatest possible number of minor alkaloids.
The three indole alkaloids ibogaine (Ia), tabernanthine (Ib) and
ibogamine (Ic) known from the earlier investigations of Tabernanthe iboga
root(2) are presumed to differ only with respect to a methoxyl on ring
A.(3) A fourth alkaloid, iboluteine (IV), has been isolated from a plant
extract(4) and has been shown to be a 5-methoxypseudoindoxyl related to
ibogaine.(5) Catalytic oxidation of ibogaine followed by reduction and
alkaline rearrangement led to its formation in good yield. Two
intermediates of the reaction sequence, the hydroperoxy (II), and the
hydroxyindolenine (III) derivatives of ibogaine were obtained in
crystalline form. Desmethoxyiboluteine was prepared by a similar treatment
of ibogamine but without isolation of the intermediate compounds. Air
oxidation of ibogaine yielded not only iboluteine but also iboquine (V)
which was formulated as a 6-methoxyquinolol.(4)
In the present study, ibogaine readily was obtained on direct
crystallization of the total alkaloids. Chromatography of the mother liquor
material on alumina gave ibogamine in high purity followed by ibogaine
which was eluted together with small amounts of tabernanthine. While the
separation of the latter two alkaloids may be achieved by a tedious
fractional crystallization, a simple method has been developed based on the
relative solubilities of the hydrochlorides in acetone. Addition of
hydrochloric acid to an acetone solution of the bases precipitates ibogaine
hydrochloride. Tabernanthine is obtained by direct crystallization of the
bases recovered from the filtrate. A similar method has been published
which takes advantage of the greater solubility of tabernanthine
hydrochloride in chloroform.(6) In our hands the separation claimed could
not be realized.
Several minor alkaloids were isolated from the amorphous material
remaining after the above chromatography. The hydroxyindolenine derivatives
of ibogaine and ibogamine which were obtained in larger amounts than the
other minor alkaloids had not previously been isolated from a plant
extract. While they may occur naturally, their origin might equally well be
attributed to the facile autoxidation of the parent alkaloids. The presence
of iboluteine, desmethoxyiboluteine and iboquine in the plant extract may
well arise as a consequence of this type of aerial oxidation.
The presence of voacangine confirms the relationship of Tabernanthe and
Voacanga alkaloids. The first indication was recorded by Janot and Goutarel
who obtained ibogaine by saponification and decarboxylation of
voacangine.(7) Its occurrence in Tabernanthe iboga had not been noted prior
to the present isolation.
Gabonine, kisantine and kimvuline are new Tabernanthe alkaloids and
deserve additional comment. Gabonine has been isolated from numerous
Tabernanthe samples and is one of more widely distributed Tabernanthe
alkaloids. Micro-analysis indicates an empirical formula of C21H28N2O4 and
the presence of two methoxyl groups. The compound is recovered unchanged
following attempted reduction with LiAlH4. The ultraviolet absorption with
maxima at 253, 287 and 345-349 nanometers differs from that of any other
Tabernanthe alkaloid. Only a very weak band is present in the OH-NH region
of the infrared absorption spectrum.
Another alkaloid, kisantine, analyzes for C21H28N2O3 and has two methoxyl
groups. The ultraviolet spectrum has maxima at 213-214 and 274-276
nanometers with a shoulder at 296 nanometers. Infrared data indicate an -NH
group and a band at 1670 percentimeters which possibly represents an
unsaturated ester moiety.
Kimvuline which was isolated from the recrystallization mother liquor of
crude ibogaine has been assigned the empirical formula C20H26N2O2. One
oxygen is represented in a methoxyl while the second probably occurs in a
hydroxy group. This oxygen function is not readily apparent in the infrared
spectrum since strong hydrogen bonding is present which does not change on
dilution in chloroform solution. The ultraviolet spectrum is typical of
indoles and remains unchanged in alkaline medium.
The authors wish to express their thanks to Mr. B. Korzun for the paper
chromatography used throughout this investigation, and to Mr. L. Dorfman
and his staff for the analytical and spectral data.
Ibogaine.(8) - Tabernanthe iboga (96.7 kg.) was extracted four times by
recycling methanol at 60-65 degrees through a stationary bed of the ground
root for two hours. The total extract (1320 l.) was evaporated in vacuo to
18 l. to which was added 9.6 l. of water, 28.8 l. of 15% acetic acid and
1.25 kg. of Filter-Cel. The mixture was stirred, filtered, and the filter
cake washed with 2.4 l. of a solution prepared by mixing 0.18 l. of acetic
acid, 0.8 l. of methanol and 1.6 l. of water. The combined filtrate and
washings were extracted twice with 19.2-l. portions of petroleum naphtha
(b.p. 60-90 degrees). The petroleum naphtha extracts were back washed with
3.8 l. of 15% acetic acid. To the aqueous phase, 25.2 l. of ethylene
dichloride was added followed by 19.1 l. of ammonium hydroxide over a
period of 90 min. The layers were separated and the aqueous phase
re-extracted five times with 12.8-l. portions of ethylene dichloride. The
extracts were combined and washed with three 25-l. portions of water, dried
over anhydrous sodium sulfate, filtered, and concentrated to 2.5 l. Ethanol
(2 l.) was added, the solution again concentrated to 2.5 l., and a further
6 l. of ethanol added. After chilling for two days 456 g. of crude ibogaine
was collected, m.p. 140-143. The filtrate was evaporated to four liters and
chilled overnight yielding a second crop of 474.5 g. melting at 137-140
degrees. The filtrate was evaporated to dryness and the dark amorphous
residue of 1.16 kg. was reserved for the isolation of the minor alkaloids.
The crude ibogaine (474 g.) in 2890 ml. of ethanol was treated with 50 g.
of Norite, filtered, and allowed to crystallize yielding 379 g. melting at
143.5-146 degrees. A second treatment with Norite and crystallization from
ethanol yielded 309 g. melting at 148-149 degrees. This product in 3,090
ml. of benzene was filtered through 620 g. of neutral alumina (Activity II)
and the column washed with an equal volume of benzene. Evaporation of the
solvent and crystallization of the residue from 1400 ml. of ethanol
yielded 259 g. of pure ibogaine melting at 152-153 degrees. Chromatography
on paper showed only a trace of impurity. For analysis a sample was dried
overnight in high vacuum at room temperature.
Anal. Calcd. for C20H26N2O: C, 77.38; H, 8.44; N, 9.03. Found: C, 77.51;
H, 8.70; N, 9.13.
Ibogaine Hydrochloride. - To a stirred solution of 100 g. of ibogaine in
1000 ml. of acetone, 51 ml. of aqueous HCl (1:1) was added dropwise.
Crystalline ibogaine hydrochloride separated immediately. The product was
filtered and washed with acetone; yield 108.5 g., m.p. 299-300 degrees,
[alpha]D -63 degrees (ethanol), -49 degrees (water).
Anal. Calcd. for C20H26N2O.HCl: Cl, 10.22. Found: Cl, 10.27.
Chromatography of Ibogaine Mother Liquor. - From 717 g. of the dark
amorphous mother liquor material, 320 g. of a light tan powder was obtained
by leaching with a total of 12 l. of cyclohexane. A solution of 300 g. in 5
l. of cyclohexane was chromatographed on 15 kg. of neutral alumina
(Activity III). Eighteen 12-l. fractions were taken with cyclohexane
(1-18), the next nine with benzene (19-27), six with methylene chloride
(28-33), two with chloroform (34-35), six with chloroform containing 1%
methanol (36-41), and finally three with chloroform-methanol, 1:1 (42-44).
Ibogamine and its Hydroxyindolenine Derivative (Fract. 8-18). -
Concentration of the cyclohexane eluate yielded a total of 70 g. of
crystalline ibogamine melting at 154-160 degrees. An additional 6.5 g. was
recovered from the filtrate. A small sample was recrystallized four times
from methanol; m.p. 162-163 degrees, [alpha]26D -36.4 degrees (chloroform).
Anal. Calcd. for C19H24N2: C, 81.38; H, 8.63; N, 9.99. Found: C, 81.23;
H, 8.67; N, 9.94.
The filtrate from the isolation of crude ibogamine was evaporated to
dryness. The residue (5.2 g.) was dissolved in benzene and chromatographed
on 150 g. of basic alumina. Benzene (875 ml.) eluted 1.4 g. of ibogamine.
Methylene chloride (1800 ml.) and chloroform (900 ml.) eluted the
hydroxyindolenine derivative of ibogamine which crystallized readily from
acetone; yield 1.5 g., m.p. 161-163 degrees. A small sample, recrystallized
from acetone, melted indistinctly about 100 degrees, solidified and then
remelted at 168-172 degrees, [alpha]25D +82.5 degrees (95% ethanol);
ultraviolet absorption: plateau, 217-219 nanometers (18,800); max., 222
nanometers (19,800); shoulder, 228 nanometers (13,700); max., 253-254
nanometers (3910); max., 281 nanometers (3,200); shoulder, 292 nanometers
(3,020). The infrared spectrum showed a carbonyl function as an impurity
consistent with acetone of solvation.
Anal. Calcd. for C19H24N2O+0.5CH3COCH3: C, 75.66; H, 8.36; N, 8.61.
Found: C, 75.34; H, 8.46; N, 8.61.
Tabernanthine (Fract. 19-21). - Crystallization of the combined fractions
(102 g.) from ethanol yielded 76 g. of crude ibogaine, m.p. 140-150
degrees, containing about 4% tabernanthine (estimated from a paper
chromatogram). The mixture (56 g.) in 1 l. of acetone was titrated with
30.5 ml. of 1:1 aqueous hydrochloric acid. The insoluble ibogaine
hydrochloride was filtered and washed with acetone. The filtrate was made
basic with ammonium hydroxide, filtered and evaporated to dryness. The
residue in 200 ml. of methylene chloride was washed with water and dried
over sodium sulfate. Evaporation of the solvent and crystallization of the
residue (4.7 g.) from ethanol yielded 1.5 g. of tabernanthine melting at
A small sample was recrystallized from ethanol and sublimed at 160
degrees at 0.005 mm., m.p. 213.5-215 degrees.
Anal. Calcd. for C20H26N2O: C, 77.38; H, 8.44; N, 9.03. Found: C, 77.09;
H, 8.37; N, 8.99.
Tabernanthine hydrochloride. - To a solution of tabernanthine (0.45 g.)
in 5 ml. of methylene chloride, 0.30 ml. of 1:1 aqueous hydrochloric acid
was added. The mixture was chilled for two hours and then filtered. The
product was recrystallized from water; yield 0.42 g., m.p. 275-277 degrees.
Another recrystallization from water failed to raise the melting point;
[alpha]25.5D -66 degrees (methanol).
Anal. Calcd. for C20H26N2O.HCl: C, 69.25; H, 7.85; N, 8.08; Cl, 10.22.
Found: C, 69.60; H, 7.86; N, 8.06; Cl, 10.33.
Hydroxyindolenine Derivative of Ibogaine and Iboquine. - A benzene
solution of 5 g. of mother liquor residue from the crystallization of the
ibogaine-tabernanthine mixture was chromatographed on 150 g. of basic
alumina. Benzene eluted 2.1 g. of ibogaine while methylene chloride and
methylene chloride containing 1% methanol afforded the hydroxyindolenine
derivative of ibogaine. Following crystallization from 95% ethanol the
compound melted at 123-124 degrees, [alpha]D +74 degrees (ethanol);
ultraviolet absorption: max., 223 nanometers (13,700); shoulder 260
nanometers; max., 283 nanometers (5,900); shoulder, 290 nanometers; max.,
312-313 nanometers (3,530).
Anal. Calcd. for C20H26N2O2.H2O: C, 69.74; H, 8.19; N, 8.13. Found: C,
69.64; H, 8.21; N, 8.24.
Recrystallization from acetone or from benzene gave a product melting
sharply at 147-149 degrees.
The latter fractions eluted with methylene chloride containing 1%
methanol gave crystals from acetone, 0.04 g., which after recrystallization
from methanol-ether melted at 268-271 degrees. The ultraviolet and infrared
absorption bands were identical with those of iboquine.
Gabonine (Fract. 24). - A 0.5-g. sample of the amorphous fraction (5.4
g.) was rechromatographed on 15 g. of basic alumina. Methylene chloride
eluted 0.16 g. of gabonine which was crystallized from ethanol-water, m.p.
211-215 degrees. After three recrystallizations from methylene
chloride-ethanol and drying in vacuo the compound melted at 223-226
degrees, [alpha]24D +65 degrees (chloroform); ultraviolet absorption: max.
at 253 nanometers (25,400), 287-288 nanometers (6,860) and 355-359
nanometers (5,850). The infrared spectrum showed strong absorption at 1620
percentimeters, medium at 1672, and very weak absorption in the OH, NH
region. The compound may contain an amide or conjugated carbonyl grouping.
Anal. Calcd. for C21H28N2O4: C, 67.72; H, 7.58; N, 7.52; CH3O, 16.4.
Found: C, 67.65, 67.81; H, 7.78, 7.53; N, 7.71, 7.86; CH3O, 16.42.
Kisantine (Fract. 25-29). - Of the 4.1 g. of material eluted, 3.5 g. was
chromatographed on 175 g. of basic alumina (Activity III). A crystalline
compound, m.p. 130-135 degrees, was obtained from the benzene eluate in too
small an amount to permit positive identification. Continued elution of the
column with methylene chloride afforded gabonine, 0.06 g. Methylene
chloride containing 1% methanol eluted kisantine which crystallized from
ethanol, m.p. 236-238 degrees, [alpha]26D -15 degrees (chloroform);
ultraviolet absorption: max., 213 nanometers (31,700) and 270-276
nanometers (6,270); shoulder, 296 nanometers (4,710). The infrared spectrum
showed a medium intensity band at 1670 percentimeters and a strong band at
1630 percentimeters in the carbonyl region. The compound was sublimed
Anal. Calcd. for C21H28N2O3: C, 70.76; H, 7.92; N, 7.86; CH3O(2), 17.4.
Found: C, 70.57, 70.68; H, 7.67, 7.92; N, 7.96; CH3O, 16.25; no N-methyl.
Desmethoxyiboluteine (Fract. 37). - Chromatography of 1.2 g. of the
amorphous fraction in benzene on 139 g. of basic alumina (Activity III)
yielded the hydroxyindolenine derivative of ibogamine, m.p. 157-162
degrees. Methylene chloride containing 0.25% ethanol eluted
desmethoxyiboluteine, 0.55 g., which after one crystallization from benzene
and five from methanol melted sharply at 141 degrees; ultraviolet
absorption: max., 230-231 nanometers (23,470); plateau, 250-252 nanometers
(6,430); shoulder, 256 nanometers (6,260); max., 400-401 nanometers
(3,320). Paper chromatography and infrared absorption confirm the identity
of the compound as desmethoxyiboluteine.
Iboluteine (Fract. 39). - Paper chromatography showed this fraction (9.5
g.) to consist almost entirely of iboluteine. A solution of 1.6 g. in
benzene was rechromatographed on 100 g. of basic alumina (Activity III).
Benzene eluted a mixture of iboluteine with small amounts of
desmethoxyiboluteine while later fractions eluted with methylene chloride
contained pure iboluteine. For analysis the product was crystallized from
methanol and sublimed, m.p. 142 degrees, [alpha]25D -144 degrees (chloroform).
Anal. Calcd. for C20H26N2O2: C, 73.59; H, 8.03; N, 8.58. Found: C, 73.51;
H, 8.01; N, 8.02.
Voacangine. - From another sample of Tabernanthe root (4 kg.), ibogaine
was obtained as before on direct crystallization of the total alkaloids.
The mother liquor material in benzene was chromatographed on 1500 g. of
neutral alumina (Activity II-III). The first 3000-ml. fraction eluted 27 g.
of amorphous material which was rechromatographed on 2500 g. of neutral
alumina (Activity II-III). Following ibogamine and ibogaine, voacangine,
0.65 g., m.p. 125-130 degrees, was eluted with benzene-ether (1:1).
Recrystallization from ethanol raised the m.p. to 136-137 degrees,
[alpha]26D -34 degrees (chloroform), pKa' 7.4 (40% aqueous methanol);
ultraviolet absorption: max., 226 nanometers (28,400) and 288-293
nanometers (9,140); shoulder, 300 nanometers (8,600).
Anal. Calcd. for C22H28N2O3: C, 71.71; H, 7.66; N, 7.60; CH3O(2), 16.85.
Found: C, 71.50, 72.14; H, 7.68, 7.85; N, 7.67; CH3O, 16.18.
The isolated compound gave an undepressed mixed melting point with
voacangine(9) and had an identical infrared spectrum and X-ray powder
diagram.(10) Further elution with ether-methanol mixtures yielded kisantine
and the hydroxyindolenine derivative of ibogaine.
Kimvuline. - The mother liquor material (29.7 g.) from the first
recrystallization of 206 g. of crude ibogaine was chromatographed on 750 g.
of neutral alumina (Activity III). Kimvuline was eluted with benzene
following the ibogaine fractions. After one crystallization from methanol
the m.p. was 228-230 degrees, 0.26 g. Recrystallization from benzene raised
the m.p.to 231-232.5 degrees, [alpha]D +3.7 degrees (chloroform);
ultraviolet absorption: max., 227 nanometers (24,800), 288-291 nanometers
(8,400) and 297 nanometers (8,300).
Anal. Calcd. for C20H26N2O2: C, 73.59; H, 8.03; N, 8.58; CH3O, 9.07.
Found: C, 73.62; H, 8.25; N, 8.57; CH3O, 8.92, 8.96.
Summit, N. J.
(1) The structural formulas used in this paper are based on evidence
presented in Part II, W. I. Taylor, This Journal, 79, 3208 (1957).
(2) T. A. Henry, "The Plant Alkaloids," J. A. Churchill Ltd., London, 1949,
(3) P. Lebeau and M. M. Janot, "Traite de Pharmacie chimique," Vol. 4,
Masson et Cie, Paris, 1956, pp. 2982-2988.
(4) R. Goutarel and M. M. Janot, Ann. pharm. franc., 11, 272 (1953).
(5) R. Goutarel, M. M. Janot, F. Mathys and V. Prelog, Helv. Chim. Acta,
39, 742 (1956).
(6) J. Delourme-Houde, Ann. pharm. franc., 4, 30 (1946).
(7) M. M. Janot and R. Goutarel, Compt. rend., 241, 986 (1955).
(8) The extraction and preparation of the crude ibogaine was carried out by
Mr. E. Solook of our Pilot Plant Section.
(9) Supplied through the courtesy of Dr. N. Neuss, Lilly Research
(10) Measured by Prof. G. A. Jeffrey, Sarah Mellon Seaife Radiation
Laboratory, University of Pittsburgh.