Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ ~625~3
The invention relates to a new process for the preparation of
apovincaminic acid esters. More particu]arly, the invention concerns a process
for preparing racemic or optically active apovincaminic acid esters of the
general formula I
I
R OOC =C2H5
wherein R represents an alkyl having from 1 to 6 carbon atoms.
According to the invention the apovincaminic acid esters of the general
formula I are prepared by reacting a hydroxyamino-E-homo-eburnane of the general
formula II
1~ ~ N II
HO-HN ~
RlOOC C--2H5
wherein R is as hereinabove described, or an acid addition salt thereof with
an organic sulfonic acid, in an aprotic organic solvent.
In the definition of R the term "alkyl having 1 to 6 carbon atoms" is
used to refer to straight or branched chained alkyl groups with 1 to 6 carbon
atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, etc.
It is well known that the apovincaminic acid esters of the general
formula I, wherein R is as defined above, possess valuable pharmacological
properties, and especially the (+)-apovincaminic acid ethylester is excellent
~. - 1-
~k
~ ~ 6~5~ 3
vasodilator.
According to the Hungarian Patent Specification No. 163,434, corres-
ponding to German Patent ~o. 2,253,750, -these compounds were prepared by sub-
jecting the pharmaceutically active vincamine to hydrolysis and converting the
vincaminic acid obtained into corresponding ester. From the vincaminic acid
ester produced the corresponding apovincaminic acid ester was prepared by
splitting off water. According to another alternative vincamine was first
converted into apovincamine by splitting off water, whereupon apovincamine was
hydrolysed and the apovincaminic acid obtained was convertèd into the desired
ester.
A disadvantage of this process is that first vincamine has to be
prepared by a multi-step synthesis and from this compound the corresponding
apovincaminic acid esters can be obtained only with a yield of at most 60%.
According to another process disclosed in the Published Japanese
Patent ~pplication 53-061757 compounds of the general formula I, R is as here-
inbefore defined, were prepared by reacting the corresponding lq-oxo-15-hydroxy-
imino-3~,16~-E-homo-eburnane with the corresponding alcohol, in the presence of
an acid.
The most important disadvantage of this process consists in the fact
that at the reaction temperature involved, which exceeds 100 to 104 C a large
amount of the ether corresponding to the alcohol used is also obtained. For
example if ethylalcohol is used as an alcohol in the reaction, large amounts of
diethyl ether are also formed due -to the presence of the dehydrating acid. The
formation of ether is particularly disadvantageous in the technologies to be
used industrially since the presence of ethers lead to increased danger of
burning and explosion and accordingly, to extreme security requirements.
A further drawback of this process is that generally the highly
agressive concentrated sulfuric acid is used for dehydration and therefore side
~ 2 -
~ ~ 62~43
reactions take place, which decrease the yield and on the o-ther hand, worsen the
quality of the end product.
It has now been found that if as a starting compound a compound which
already has the ester group corresponding to the desired apovincaminic acid
ester of the general formula I is employed, the presence of alcohol can be
eliminated and accordingly, no ether formation takes place. For this purpose
compounds of the general formula II, wherein R has the same meaning as defined
above, can excellently be used.
Starting compounds of the general formula II are prepared according to
a process disclosed in the Belgian Patent No. 883,576 from the corresponding
hexahydroindolo-quinolizinium compounds with methylene-malonic acid diesters.
In the process according to the invention the compounds of the general formula
II can be employed as such or in the form of their acid addition salts with
inorganic or organic acids, preferably of their hydrochloride.
It has further been found that if concentrated sulfuric acid is
replaced by less corrosive organic sulfonic acids, e.g. aliphatic or aromatic
sulfonic acids, the danger of corrosion of the equipments used is considerably
reduced.
The use of organic sulfonic acids instead of concentrated sulfonic
acid decreases also the side reactions due to corrosion, thus not only the
yield but also the quality of the end product is improved. The improvement in
quality is of particular importance, since the compounds of the general formula
I prepared by this process are intended for pharmaceutical use.
~ - 3 -
~ 1 B2 54 3
As aliphatic sulfonic acids sulfonic acids containing an aliphatic
carbon chain having 1 to 12 carbon atoms, e.g. methanesulfonic acid, ethane-
sulfonic acid, dodecylsulfonic acid, etc. can be used. Aromatic sulfonic acids
include sulfonic acids containing one or more aromatic rings which may be sub-
stituted with one or more identical or different substituents, e.g. benzene-
sulfonic acid, p-toluenesulfonic acid, ~-naphthylsulfonic acid, ~-naphthyl-
sulfonic acid, etc. For 1 mole of a ccmpound of the general formula (II) prefer-
ably 2 to 3 moles of a sulfonic acid are used.
AS a solvent aprotic organic solvents, such as optionally halogenated
aromatic hydrocarbons, e.g. benzene, toluene, xylene, chlorobenzene, etc. or
cyclic ethers, e.g. dioxane, etc. can be employed.
The reaCtiQn is performed at a temperature of 80 to 150 &, preferably
100 to 120 C. The reaction time is a function of the temperature.
m e reaction is preferably carried out under anhydrous conditions.
By the new process according to the invention racemic and optically
active compounds of the general formula (I) can equally be prepared starting from
racemic and optically active compounds of the general formula (II), respectively.
A major advantage of the instant prccess over the processes kncwn in
the art consists in the fact that by this process the apovincaminic acid estexs
of the general formula (I) can be prepared starting from readily available com-
pounds, by hardly corrosive reactants, which are easy to handle, with an in-
creased yield and in high purity. m e pro oe ss provided is easy to carry out on
industrial scale and does not involve security problems.
According to the most preferred ~mbollment of the pxo oess according to
the inventic,n a compound of the general formula (II) or an acid addition salt,
preferably hydrochloride thereof is boiled with dry p-tolu~nesulfonic acid in
toluene for l to 2 hours.
i J ~543
Further details of the invention are illustrated by the following, non-
-limiting Examples.
Example 1
70 g. (0.1 moles) of (-)-l~-(carkxxnethoxyethyl) 1~-ethyl-1,2,3,4,6,7,
12,12b-octahydro-indolo[2,3-a]quinolizine-D-d~benzoyl tartarate are suspended in300 ml. of toluene. To the suspension 70 ml. of concentrated aqueous ammonium
hydroxide solution are added and the reaction mixture is stirred at room tempera-
ture for 10 minutes. The toluene phase is separated fram the aqueous phase, and
is dried by azeotropic distillation, whereupon the mixture is made up to 30Q ml.with toluene. To the toluene solution 36 ml. (31 g.) of tert-butyl-nitrite and
25 g. of sodium tert-butylate are added and the mixture is stirred in nitrogen
atrnosphere, at 30 & for 25 minutes. To the reaction mLxture 300 ml. of ethanol
are then added and it is stirred at 60 & for 1 hour. The pH is adjusted to 2 by
a 36 % aqueous hydrochloric acid solution at room tem~erature, the mixture is
cooled to 0 and the precipitated substance is filtered off at this temperature
and washed with two 100 ml. portions of water. The product obtained is air driedand i5 then treated with 150 ml. of a 10 % aqueous ammonium hydroxide solution.
me product is filtered off, washed with three 50 ml. portions of water and dried.
20 g. of (-)-14-ethoxycarbonyl-14-hydroxyamino-3~,16~-eburnane are obtained, melt-
ing at 172 to 173 C. Yield: 52 %.
[~]D = -144.1 (c = 1, chloroform).
Example 2
19 g. (0.05 moles) of (-)-14-ethoxycarbonyl-14-hydroxyamino-3~,16~-
-eburnane prepared according to Example 1 and 19.8 g. (0.125 moles) of dry p-
-toluenesulfonic acid are boiled in 350 ml. dry toluene for 1.5 hours. The reac-tion mixture is cooled to 20 C, whereupon 200 ml. of water are added and the pHof the mixture is adjusted to 9 with about 20 ml. concentrated ammonium hydroxide
I ~ 62~3
solution. m e o~ganic phase is separated and the aqueous phase is extracted with
50 ml. of toluene. The toluene phases are combined, dried on anhydrous sodium
sulfate, filtered, the filtrate is decoloured with 1 g. of activated carbon and
is filtered. The filtrate is evaporated to dryness in vacuo, the e~aporation
residue is dissolved in 20 ml. of ethanol, boiled for one minute and is crystal-
lized after cooling to 0 C. 16.6 g. of (+)-apovincaminic acid ethylester are ob-
tained, melting at 144 to 146 C. Yield: 95 %.
[~]D0 = +(144.1-145.1) (c = 1, chloroform).
Purity: 99.8 to 100.1 ~ (in glacial acetic acid, in the presence of
indicator, using perchloric acid for titration).
Example 3
From a solution of 47.5 g. (0.25 moles) of p-toluenesulfonic acid
hydrate in 400 ml. of toluene water is eliminated by azeotropic distillation.
Thereafter 42 g. (0.1 moles) of (-)-14-ethoxycarbonyl-14-hydroxyamino-3~,16~-
-eburnane hydrochloride are added to the dry mixture, which is then refluxed for
two hours with stirring. m e reaction mixture is ccoled to +10 C, 100 ml. of
water, 30 ml. of a 25 % aqueous ammonium hydroxide solution and 2 g. of celite
are added and the reactian mixture is stirred at +10 & for 5 minutes whereupon
it is filtered. The aqueous and toluene phases of the filtrate are separated,
the aqueous phase is extracted with 50 ml. of toluene and the toluene phases are
cambined. The combined toluene phases are washed with 50 ml. of water, dried on
20 g. of anhydrous sodium sulfate and filtered. The filtrate is evaporated to
dryness in vacuo, to the evaporation residue 40 ml. of ethanol are added, the
solution obtained is boiled for one minute and is then cooled to 0 & . The mix-
ture is allowed to stand at 0 & for one hour, the precipitated product is
filtered off, is washed by co~ering with two 20 ml. portions of ethanol of a
temperature of 0 C and dried. 30 g. (86 %) of (+)-apo~incaminic acid ethylester
~i
~ ~ 625~3
are obtained, melting at 144 to 146 &.
[~]D0 = +(141 to 146) (c = 1, chloro~orm)
Analysis for C22H25N2O2 ( lecular weight: 350.44):
calculated: C 75.33 %, H 7.45 %, N 7.99 %;
found: C 75.31 %, H 7.42 %, N 7.90 %.
Fxample 4
Foll~wing the pro oe dure described in Example 3 but starting from 38 g.
(0.1 moles) of (-)-14-ethoxycarbonyl-14-hydroxyamino-3~,16~-eburnane 31.5 g.
(90 %) of (-~)-apovincaminic acid ethylester are obtained, melting at 144 to
146 &.
[]D0 = +(141 to 146) (c = 1, chloroform).
Example 5
Follcwing the proeedure described in Example 3 but using 400 ml. of
benzene instead of 400 ml. of toluene as a solvent and carrying out the reaction
in 12 hours, 23.4 g. (67.0 %) of (+)-apovineaminic acid ethylester are obtained,
melting at 141 to 145 &.
[~]D = +(141 to 144) (e = 1, chloroform).
Example 6
FollowLng the procedure deseribed in F,xample 4 but using 400 ml. of
xylene instead of 400 ml. of toluene as a solvent and carrying out the reaction
in 30 minutes at a temperature of 140 & 30.5 g. (87.3 %) of (+)-apovineaminie
aeid ethylester are obtained, melting at 144 to 146 &.
[~]D = +(141 to 146) (e = 1, chloroform).
Example 7
Follcwlng the procedure deseribed in Example 3 but using 400 ml~ of
ehlorobenzene instead of 400 ml. of toluene as a solvent and carrying out the
reaetion at 130 & for 40 minutes, 30.8 g. (88 %) of (+)-apovincaminie aeid ethyl-
ester are obtained.
~ ~ ~254 3
Example 8
Following the procedure described in Example 3 but using 43 g. (0.25
moles) of dry p-toluenesulfonic acid instead of 47.5 g. (0.25 moles) of ~-toluene-
sulfonic acid hydrate and 400 ml. of dioxane instead of 400 ml. of toluene,
18.0 g. (51.5 %) of (+)-apovincam~nic acid ethylester are obtained, melting at
141 to 143 C.
[~]D = +(140 to 143) (c = 1, ehloroform).
Example 9
Following the procedure described in Example 3 but replacing 47.5 g.
(0.25 moles) of ~toluenesulfonic acid hydrate by 27.5 g. (0.25 moles) of ethane-
sulfonie aeid, 30.0 g. (86 %) of (+)-apovineaminie aeid ethylester are obtained,
melting at 144 to 146 C.
[~]D0 = +(141 to 146) (e = 1, chloroform).
Example 10
Following the procedure described in Example 3 but replacing 48 g.
(0.25 moles) of ~-toluenesulfonic acid hydrate by 39.5 g. (0.25 moles) of benzene-
sulfonie aeid, 30.5 g. (87.5 %) (+)-apovineaminie aeid ethylester are obtained,
melting at 144 to 146 &.
[~]D0 = +(141 to 146) (c = 1, ehloroform).
,~
