The Production of a Vinyldiacetonalkamine and of Anaesthetics therefrom.
Year: 1896

page_text: Date of Application, 18th Sep., 1896
Complete Specification Left, 17th June, 1897-Accepted, 24th July, 1897
PROVISIONAL SPECIFICATION.
The Production of a Vinyldiacetonalkamine and of Anaesthetics
therefrom.
I AUGUST ZIMMERMANN of 9 and 10 St. Mary at Hill in the City of London
Merchant do hereby declare the nature of this Invention which has been communicated
to me from abroad by The Chemische Fabrik auf Actien vormals E. Schering of
170 and 171 Müllerstrasse, Berlin, in the Empire of Germany, to be as follows:-
My correspondents have discovered that Fischer's vinyldiacetonalkamine produced
by the reduction of vinyldiacetonamine (Berichte der Deutschen Chem. Gesell-
schaft XVII 1794) which according to Fischer melts at 123° C. is not a uniform body,
but that a base melting at 138° C. inay be obtained from it by crystallizing the salts
for example the hydrochloric acid salt.
For producing this base, Fischer's vinyldiacetonalkamine melting at from 121° to
123° C., which is obtained by the reduction of vinyldiacetonamine either with or
without heating, or with cooling by ice, is transformed into its hydrochloric acid salt
which is dried quickly and extracted with absolute alcohol. By this treatment the
hydrochloric acid salt remains behind as a base melting at 138° C. The hydrochloric
acid salt of another base melting at from 161° to 162° C. is found in the filtrate.
The first base is soluble in water and crystallizes out of benzol in hard crystals
which shine like glass.
My correspondents have further discovered that from this base melting at 138° as
well as from its alkylderivatives, local anaesthetics may be obtained by substituting
the hydrogen atom of hydroxyl with the benzoyl, phenyl, acetyl and cinnamyl groups.
The benzoylderivative of the base melting at 138° is produced for example as
follows molecular quantities of the dry hydrochloric acid salt of the base melting at
138° and benzoyl chloride are heated at 130° C. for so long as evolution of hydrochloric
acid takes place. The product of the reaction is then dissolved in water, and the
solution shaken with ether to eliminate the excess of benzoyl chloride; the benzoyl
derivative is then set free from the hydrochloric acid solution by means of caustic
soda solution and is then shaken with ether. The benzoylvinyldiacetonalkamine is
obtained after crystallizing out of petroleum ether in well formed crystals which shine
like glass and melt at 78°.
In place of benzoyl chloride, benzoic anhydride may of course be used; also in
place of the hydrochloric acid salt, the free base may be used but less advantageously.
The methyl product is obtained from the benzoylvinyldiacetonalkamine by
methylation. It may also of course be obtained by the action of benzoyl chloride or
benzoic anhydride upon the oily methylvinyldiacetonalkamine obtained by methylation
of the base melting at 138°. The benzoylmethylvinyldiacetonalkamine is a thickly
liquid oil which has not up to the present been crystallised.
The toluyl, cinnamyl, phenyl and acetyl derivatives are produced in an analogous
way. The hydrochloric acid salts obtained by precipitating the ethereal solution of the
said acidylated bases with ethereal hydrochloric acid have all strong anaesthetic
properties.
Dated thin 10th
S Contamben 2000

page_text: COMPLETE SPECIFICATION.
The Production of a Vinyldiacetonalkamine and of Anaesthetics
therefrom.
I, AUGUST ZIMMERMANN, of 9 and 10 St Mary at Hill in the City of London
Merchant, do hereby declare the nature of this invention (which has been
communicated to me from abroad by The Chemische Fabrik auf Actien vormals
E. Schering of 170 and 171 Müllerstrasse, Berlin in the Empire of Germany), and
in what manner the same is to be performed to be particularly described and
ascertained in and by the following statement :-
My correspondents have discovered that Fischer's vinyldiacetonalkamine produced
by the reduction of vinyldiacetonamine (Berichte der Deutschen Chem. Gesell-
schaft XVII 1794) which according to Fischer melts at 123° C. is not a uniform body,
but that a vinyldiacetonalkamine melting at 138° C. may be obtained from it by
crystallizing the salts for example the hydrochloric acid salt as well as by crystallisation
of Fischer's base from ether, benzol or the like.
The said base melting at 138° C. is best produced by transforming at ordinary, or
elevated temperature, or whilst cooling with ice, Fischer's vinyldiacetonalkamine into
its hydrochloric acid salt, well drying the latter and then extracting with absolute
alcohol. By this treatment the hydrochlorate of a vinyldiacetonalkamine melting at
138° C. remains behind, while the filtrate contains the hydrochlorate of another
vinyldiacetonalkainine melting at from 161° to 162° C.
The first base is easily soluble in water and crystallizes out of benzol in hard
crystals which shine like glass.
My correspondents have further discovered that from this base melting at 138° as
well as from its alkylderivatives, local anaesthetics may be obtained by substituting
the hydrogen atom of hydroxyl with the benzoyl group (C,H, CO-), the toluyl
group (CH, CH, CO-), the phenylacetyl group (CH, CH, CO-), the cinnamnyl
group (CH, CH=CH. CO-). These groups by the introduction of which
compounds of anaesthetic properties can be obtained, are named anaesthesiophorus
groups, according to Ehrlich.
The composition of the so formed acidyl compounds corresponds to the chemical
formula
R-O-CH
CH,
CH₂
CH,
C
CH-CH,
CH,
N-H*)
in which formula R is meant for an anaesthesiophorus group and H*) for a hydrogen
atom which can be replaced by an alkyl group, for instance, by the methyl
group (CH,), the ethyl group (C,H,).
The bases expressed by the before mentioned formula, in which the hydrogen atom,
bound to the nitrogen atom, is not replaced by an alcoholic radical, are insoluble in
water and decompose, upon boiling with watery or alcoholic alkali, into the
vinyldiacetonalkamine melting at 138° and into the salt of that acid the radical of
which has been substituted for the hydrogen atom of the hydroxyl.
Thus, for
example, the benzoylvinyldiacetonalkamine is split into the base melting at 138° and
benzoate of alkali. The bases combine with inorganic and organic acids thus forming
the corresponding salts, which possess strong anaesthetic properties. The
hydrochlorates of the said bases are easily soluble in warm water, less soluble in cold.

page_text: The properties of the bases expressed by the above formula, in which the hydrogen
atom bound to the nitrogen atom is replaced by an alkyl group, correspond with the
properties of the aforesaid bases; they are likewise insoluble in water and split, if
boiled with alkali, into the alkylvinyldiacetonalkamine and the salt of the respective
acid. The salts possess strong anaesthetic properties. The hydrochloric acid salts
are easily soluble in water.
PREPARATION OF THE ACIDYL DERIVATIVES FROM THE BASE MELTING AT 138°.
The benzoylderivative may, for instance, be obtained in the following manner :
Molecular proportions of the dry hydrochloric acid salt of the base melting at 138°
and benzoyl chloride are heated to 130° C. for as long as hydrochloric acid gas is
evolved. The product of the reaction is then dissolved in water and the aqueous
solution shaken with ether to remove the excess of benzoyl chloride. The
benzoylderivative is set free from the hydrochloric acid solution by means of caustic
soda solution and extracted with ether. After crystallizing out of ligroine, the
benzoylvinyldiacetonalkamine is obtained in well formed crystals, which shine like glass
and melt at 75° C. The hydrochloric acid salt possesses strong anaesthetic properties.
In place of benzoyl chloride, benzoic anhydride may of course be used; also in
place of the hydrochloric acid salt, the free base may be taken, but less
advantageously.
The alkyl derivatives from the before described benzoyl vinyldiacetonalkamine are
produced by alkylating the latter, for example with alkyl iodide, or by causing
benzoyl chloride or benzoic anhydride to act upon an alkylvinyldiacetonalkamine.
The alkylvinyldiacetonalkamines are best produced by alkylating the base of the
melting point of 138°. The methylvinyldiacetonalkamine is an oil which forms a
hydrate melting at about 39-40° C.; the ethyl derivative from the base melting
at 138° is likewise an oil. The benzoyl-methylvinyldiacetonalkamine as well as the
benzoylethylvinyldiacetonalkamine, represent oils, their hydrochlorates are solid and
easily soluble in water.
The preparation of the toluyl-, phenylacetyl- and cinnamyl derivatives is similarly
brought about. The hydrochloric acid salts, obtained by precipitating the ethereal
solution of the said acidyl bases with ethereal hydrochloric acid have all strong
anaesthetic properties.
After crystallizing out of ligroine, the paratoluyl-derivative from the vinyldiaceton-
alkamine melting at 138° is obtained in glassy crystals.
The phenylacetyl-vinyldiacetonalkamine is an oil. In order to purify it, the raw
product is washed with warm water, then taken up with ether, to remove small
quantities of unchanged vinyldiacetonalkamine, and the ethereal solution dried with
potash. By adding ethereal hydrochloric acid, the hydrochlorate of the phenylacetyl-
compound is precipitated as a fine crystalline powder.
The cinnamylvinyldiacetonalkamine is an oil, its hydrochlorate is likewise a
crystalline powder.
The alkyl derivatives from the before mentioned acidyl compounds are oily bodies.
Having now particularly described and ascertained the nature of my said invention
and in what manner the same is to be performed I declare that what I claim is :-
1. The process of obtaining local anaesthetics from the herein described
vinyldiacetonalkamine melting at 138°, as well as from its alkýl derivatives, which
consists in replacing the hydrogen atom of the hydroxyl in these compounds with
anaesthesiophorus groups, such as the benzoyl-, toluyl-, phenylacetyl- and cinnamyl
group.
2. The process of obtaining local anaesthetics, which consists in reducing
vinyldiacetonamnine to vinyldiacetonalkamine (melting at from 121° to 123°), allowing
a salt of the latter or the base itself to crystallise, whereby a vinyldiacetonalkamine of
a melting point of 138° C. is isolated, and substituting in this base anaesthesiophorus
groups, as the benzoyl-, toluyl-, phenylacetyl- and cinnamyl group, for the hydrogen
atom of the hydroxyl, substantially as described.
3. The production of alkyl derivatives from the herein described acidyl compound
8

page_text: of the vinyldiacetonalkamine melting at 138° C., which consists in treating these
acidyl compounds with alkyl reagents, such as alkyl iodide.
4. The production of alkyl derivatives from the herein described vinyldiaceton-
alkamine melting at 138° C., by treating the said base with alkyl reagents, such as
alkyl iodide.
5. As a new isolated chemical product vinyldiacetonalkamine melting at 138°.
6. As new chemical products the acidyl compounds of the herein described
vinyldiacetonalkamine melting at 138°, the composition of which compounds answers
the formula-
R-O-CH
CH,
CH,
CH
CH-CH,
CH,
N-H
in which R signifies an anaesthesiophorus group and H*) a hydrogen atom which can
be replaced by an alkyl group.