METHODE DE PREPARATION DE L'APOVINCAMINE A PARTIR DE LA VINCAMINE ET DE L'EPIVINCAMINE

METHOD FOR THE PREPARATION OF APOVINCAMINE FROM VINCAMINE AND EPIVINCAMINE

Abrégé anglais

ABSTRACT
A method is disclosed for the preparation of apovinca-
mine, a substance being used in the pharmaceutical field
as the active ingredient of drugs having cerebral vaso-
dilating activity.
The method of the invention permits the apovincamine to
be directly obtained from vincamine or epivincamine by
reaction with a Lewis acid.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method for the preparation of apovincamine starting
from vincamine from the isomer thereof, epivincamine, characterized
in that the starting alkaloid is reacted, as a solution in an
organic anhydrous solvent at the boiling temperature of the same
solvent, in the presence of Lewis acids, the ratio between the
starting alkaloid and the Lewis acid being of between 1 : 1 and
1:1.5 by mole.
2. A method according to claim 1, characterized in
that anhydrous methanol and benzene are used as the solvent.
3. A method according to claim 1, characterized in
that the reaction temperature is of between 65°C and 80°C.
4. A method according to claim 1, characterized in
that the Lewis acids are selected among tin tetrachloride,
phosphrus tribromide and boron trifluoride etherate.

Description

L3~
"A METHOD FOR THE PREPAR~TION OF APOVINCAMINE FRO~I VINCAMINE AND
E~I VANCAMINE"
The present invention relates to the preparation of the
apovincamine, having the formula (I), starting from vincamine
(formula IIa) and from the isomer t11ereof, epivincamine (formula
IIb).
f~
1~ ~ rI 7
C1~30~C
~i~'`~ rIT 7
~ ~J
IIa : R = _OH; R' = _COGCH3 (vincamine)
IIb : R = -COOCEI3; R' = _OH (epivincamine)
~povincamine is an indole alkaloid, naturally present
in the Tabernaemontano rlgida and in tlle Vinca erectaj which
was firstly described by J Trojane~ et al., Tetrahedron Letters,
1961, 702.
The apovincamine and the derivatives thereof, as pre-
pared by a partial synthesis methods, const.itute a class of
substances of high interest from the point of view of the use
in therapy as cerebral vasodilating agents. In the French
A~plication No~ 2023918 of Gedeon Richter, the apovincamine is
obtained through the treatm~nt of vincamine with concentrated
3Q H2SOg in C~i2C12.
In this case the action of the chlorinated solvent,
together with the hi.ghly acidic medium, yive place to coloured

3~
solutions and promote the forming of by-products.
The same drawbacks occur when the rnethod disclosed in
the French patent No. 2191894 of Synthelabo is u~ed, which
provides the treatment of vincamine with concentrated formic
acid at the boiling point and for extended time intervals.
Furthermore, like the two methods above referred to,
J. Mokry (Chem. Zvesti, 16,140(1962)),describes a method for
the conversion of vincamine into apovincamine by strong mineral
acids and thereafter, (Tetrah Lett., 27,1917(1963)), discloses
a method according to which a methanol solution of vincamine is
reacted with gaseous HC1.
In the French patent Application No. 2,178,027 of
Sandoz, a method of total syntllesis of vincamine is described
and in the several Belgian patents Nos. 761628 and 763730, as
well as in the German Patent No. 2,201,795, in the name of
Omnium Chimique, methods are dislosed for the partial synthesis
of vincamine starting from tabersonine.
In the latter case the apovincamine is considered a~
an undesired by-product and is moreover isolated with very low
yields~
- In the French patent No. 2,211,004 in the name of
Synthelabo, a method is described for the preparation of vincamine
and stereoisomers thereof. According to the step 2 of this method,
the apovincamine is obtained from apovincaldeyde through the
oxidation with MnO2 of the corresponding cyanohydrin with a
yield of 80~, whereas in the step 5 the apovincarnine is prepared
from epivincamine by treatment with boiling concentrated for-
mic acid, the yield being 80~
According to J. Trojanek, Tetrah. Letters, 20~ 702
(196i), apovincamine can be prepared by heating vincamine to
220C as well as by treating vincamine with boiling acetic
anhydride.
. .
-- 2

3~
Lastly in the Hungarian patent No. 151,295 in the name
of Gedeon Richter, ~here are reported, amongst others, two
exam~les for the preparation of the apovincamine by dehydration
of vincamine, the first one witil POC13 (yield 42~) and the second
with acetic anhydride in the presence of p-toluensulfonic acid
(yield 30%).
Tlle method of the present invention provides a relevant
tecnnical advance over the prior art, it permitting the conversion
of vincamine and of epivincamine under operating conditions
wlllc.l are extremely advantageous and selective as regards re-
actants, solvents and temperatures, ana permitting the a~ovincamine
to be obtained with very high yields and with h~gh purity degree.
In fact, it has been found that, by treating a solution
of vincamine or epivincamine in an anhydrous organic solvent,
such as methanol and benzene, with Lewis acids, preferably
selected among SnC14, PBr3, sF3, at a temperature of between
20C and 80C, for a time varying betwePn 30 minutes and 4
hours, the molar ratio between vincamine or epivincamine and
tne Lewis acid being of between 1:1 and 1:1,5, apovincamine is ob-
tained with optimum yields and high purity.
Some examples are hereinafter reported to illustratethe method of the present invention, these examples of course
having no lim~tating meaning of the invention.
Example 1
~ ~ .
5 g of ~incamine are suspended in 500 mls of anhydrous
~enzene and heated under stirring to 60-70C until a clear
solution is o~tained~ 5 mls of a 45% solution of ~oron tri-
fluoride etherate are added and the heating under stirring is
continued until the reaction is completed (about 1 hour).
The end of the reaction i5 indicated by the dis--
appearance, as rnonitored by thin layer chromatography (TLC)~ of
tlle spot pertainin~ to the vincamine and by the appearance of a
~ ~ 3 -

35;
spot having higher Rf. (Adsorbant, Silicagel G F254-eluant:
CHC13/~IeOII=95/5)~
The reaction mixture is cooled, added with 100 mls
of 10% NH40H; stirred for 10 minutes and then diluted with H20.
Tlle phases are separated and the organic phase
is exhausted by several extractions wlth benzene; the com~ined
benzene solutions are washed with water until neutral and dried
over anhydrous Na2S04. After filtration and concentration under
reduced pressure, the raw apovincamine is recrystallized from
MeOH, the yield being 4.4 g (about 92%).
Fxample 2
; The example 1 is repeated, except t'nat epivincamine is
substituted for the vincamine. In this case the apovincamine is
obtained with a yield of 78%.
Example 3
1 g of vincamine is solved in 300 mls of hot methanol
under stirring. There are added 0.4 mls of PBr3 and the reaction
is monitored by TLC. At the end of the reaction, the steps of
the example 1 are repeated.
Example 4
The example 3 is repeated, except that epivincamine is
substituted for the vincamine. The yield of the conversion to
apovincamine is 65%.
Example 5
1 g of vincamine is solved in 300 mls of anhydrous
hot benzene. 0.4 mls of PBr3 are added under stirring and the
reaction mixture is kept under slight reflux until the reaction
is completed. After kreatment of the reaction mixture according
to the steps of the example 1, 0.85g of pure apovincamine are
obtained (yield 90~3.
- Example 6
The same reaction of the example 5 i~ repeated with

epivincamine, the yield of conversion to apovincamine being
a~out 85%.
Example 7
1 g of vincamine is solved under stirring in 300 mls
of hot anhydrous benzene. 0.5 g of SnC14 are added and the
mixture is maintained under boiling until -the disappearance of
the spot corresponding to the vincamine is assessed by ~rLc.
After treatment of the reaction mixture according to the example
1 and recrystallizat-ion of the raw product, 0.7~ g of pure
apov,ncamine are obtained.
Example 8
The same reaction of Example 7 is repeated with
epivincamine and there isobtained apovincamine with a yield of
about 80