Production of y-Oxypiperidine Carboacids and Derivatives therefrom.
Year: 1895

page_text: PROVISIONAL SPECIFICATION.
Production of y-Oxypiperidine Carboacids and Derivatives therefrom.
], AUGUST ZIMMERMANN, of 6 and 7 Cross Lane, St. Mary at Hill, in the City
of London, Merchant, (a communication to me from abroad by The Chemische
Fabrik auf Actien vormals E. Schering, of 170 and 171 Müllerstrasse, Berlin, in
the Empire of Germany,) do hereby declare the nature of this invention to be as
follows:--
My correspondents have discovered that bodies derived from y-piperidone which
may be transformed by means of hydrocyanic acid into cyanhydrines which can be
10 saponified to yield y-oxypiperidine carboacids and that the hydrogen in the carboxyle
in the latter may. by known methods be replaced by alcoholic radicals and the
hydrogen in the hydroxyle by acid radicals.
Bodies with the general constitution
15 are thus formed which are useful in therapeutics.
My correspondents have discovered for example that triacetoneamine adds
1 molecule of hydrocyanic acid forming the nitrile of tetramethyl-y-oxypiperidine
carboacid, and that the acid obtained by saponifying the nitrile is by successive
treatment with methylalcoholic hydrochloric acid and benzoylchloride or benzoic

page_text: anhydride transformed into benzoyltetramethyl-y-oxypiperidine carboacid methyl-
ester. The following equations show these reactions.
RODUCTION OF DENZOYL-TETRAMETHYLOXYPIPERIDINE CARBOACID
METHYLESTER.
I. PRODUCTION OF TETRAMETHYLOXYPIPERIDINE CARBO ACID.
0.8 kg. of a concentrated solution in water of hydrochloric acid is added by
degrees and with stirring to an intimate mixture cooled with ice of 1 kg. triacetone-
amine and 0.5 kg. of potassium cyanide (98%); the cyanhydrine formed is then
saponified by boiling the mixture with concentrated hydrochloric acid (1) or
caustic soda solution (11).
In the first case (1) the surplus hydrochloric acid is driven off on a water bath,
the residue dissolved in dilute caustic soda solution and the solution acidified at the

page_text: II. PRODUCTION OF TETRAMETHYLOXYPIPERIDINE
METHYLESTER.
CARBOACID
On 1 kg. of the dry tetramethyloxypiperidine carboacid thus prepared there is
poured five times its weight of methylalcohol; and hydrochloric acid gas is then
passed for several hours through the liquid heated to boiling. After evaporation
of the methylalcohol in the water bath tetramethyloxypiperidine carboacid
methylester hydrochloride
HQ C-COOCH 3
H₂C
CH2
CH3>C
✓ CH3
-CH3
CHS'
NH.HCL
remains behind as a colourless crystalline mass.
The ester set free from the same
by soda solution is a colourless beautifully crystallising body which is exceedingly
easily soluble in nearly all solvents. This ester as well as its derivatives combines
with inorganic and organic acids forming salts which are more or less soluble in
water.
III. BENZOYLIONAT OF THE TETRAMETHYLOXYPIPERIDINECARBOACID-
METHYLESTER.
On 1 kg. powdered tetramethyloxypiperidine carboacid methylester hydro-
chloride is poured 1 kg. of benzoylchloride and the mixture is heated in an oil bath
to 140-150° C. for so long as hydrochloric acid gas is given off. The brown
coloured homogeneous syrup so obtained is then poured into water and repeatedly
shaken up with ether for the removal of the surplus benzoylchloride. From the
nearly colourless solution in water previously separated from the ether the benzoyl
tetra methyloxypiperidine carboacid methylester

page_text: extracted with ether. When the ether is distilled off the body remains behind as
a yellowish syrup which on cooling solidifies into radiating crystals. This body is
purified by crystallizing out from ligroin; it forms colourless prisms melting at 98°.
The benzoyltetramethyloxypiperidinecarboacid methylester combines with inorganic
and organic acids to form crystalline salts which are more or less soluble in water.
Dated this 26th day of June 1895.
.AUGUST ZIMMERMANN.
Production of y-Oxypiperidine Carboacids and Derivatives therefrom.
:
I, AUGUST ZIMMERMANN, of 6 and 7, Cross Lane, 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 triacetonamine and analogous derivatives
from y-piperidone as for instance benzal diacetonamine and vinyldiacetonamine
may be transformed by means of hydrocyanic acid into cyanhydrins (nitriles)
which can be saponified to yield y-oxypiperidine carboacids and that the hydrogen
in the carboxyl and imide in the latter may be replaced by alcoholic radicals and
the hydrogen in the hydroxyl by acid radicals.
Bodies of alkaloid nature with the general constitution
(A) PRODUCTION OF BENZOYL-TETRAMETHYL y-OXYPIPERIDINE-CARBO ACID
METHYLESTER AND N-ALKYL-BENZOYL TETRAMETHYL-Y-OXYPIPERIDINE
CARBOACID ESTERS FROM TRIACETONAMINE.
I. PRODUCTION OF TETRAMETHYL-Y-OXYPIPERIDINE CARBOAcid.
0.8 kg. of a concentrated solution in water of hydrochloric acid is added by
degrees and with stirring to a concentrated solution in water, cooled with ice, of
1 kg. triacetonamine and 0.5 kg. potassium cyanide (98%). The solution is then
saturated with hydrochloric acid, and the cyanhydrin saponified by boiling the
same for several hours in a return condenser. The surplus hydrochloric acid is
driven off on a water bath, the residue dissolved in dilute caustic soda solution and
the solution acidified at the boiling temperature with acetic acid. Tetramethyl-
y-oxypiperidine-carboacid separates out by this means as a nearly colourless, heavy
sandy crystalline powder, it is sucked dry, washed with water and dried.
Tetramethyl-y-oxypiperidine carboacid is almost insoluble in water, alcohol,
ether, benzol, acetic ether, dilute acetic acid, ammonia and dilute alkaline
carbonates, it is easily soluble in caustic alkalies and dilute mineral acids.
melts with decomposition at about.285° C.
It

page_text: set free from the hydrochloric acid salt by means of a solution of soda is a colourless
fine crystallizing body, which is very easily soluble in all solvents, melts at 69-70° C.
and which is saponified immediately by boiling in water, and slowly in a cold
solution in water with precipitation of tetramethyl-y-oxypiperidine-carboacid.
III. BENZOYLATION OF THE TETRAMETHYL-7-OXYPIPERIDINE CARBOACID
METHYLESTER.
On 1 kg. of the powdered tetramethyl-y-oxypiperidine carboacid methylester
hydrochloride is poured 1 kg. of benzoylchloride and the mixture heated with
stirring, and preferably with the addition of some melted chloride of zinc, in an
oil bath to 140-145° C. for so long as hydrochloric acid gas is given off. The
brown coloured syrup so obtained is then poured into ice water and the solution
repeatedly shaken up with ether for the removal of the surplus benzoylchloride.
From the solution in water, previously separated from the ether, the benzoyltetra-
methyl-y-oxypiperidine-carboacid methylester

page_text: is extracted with ether from the solution. When the ether is distilled off the body
remains behind as a yellow syrup which on cooling solidifies into a crystalline mass.
This body is purified by crystallising out from ligroin.
Benzoyltetramethyl-y-oxypiperidine carboacid methylester is very easily soluble
in alcohol, ether, chloroform and benzol. It crystallises out of hot ligroin in
fine colourless prisms which melt at about 91-92° C.
The base combines with inorganic and organic acids to form neutral reacting
salts.
The nitric, nitrous, hydrochloric, bromic, iodic, sulphuric, boric, phosphoric,
double carbonic, formic, acetic, citric, tartaric, succinic, salicylic, tropic, atropic,
benzoic, lactic and malic acid salts have been produced. With the exception of the
formic acid salt, which dissolves in four parts of water and forms large shining
crystals, all these salts are very difficultly soluble in cold water.
PRODUCTION OF HOMOLOGOUS ESTERS OF TETRAMETHYL-Y-OXYPIPERIDINE-
CARBOACID.
If in place of methylalcohol, its homologues (ethyl, propyl alcohol and the like,
react upon tetramethyl-y-oxypiperidinecarboacid as described under A II, the
hydrochloric acid salt of the homologues of tetramethyl-y-oxypiperidinecarboacid
methylester are produced as colourless easily soluble crystalline masses..
The free tetramethyl-y-oxypiperidinecarboacid ethylester
is extracted with ether from the solution. When the ether is distilled off the body
remains behind as a yellow syrup which on cooling solidifies into a crystalline mass.
This body is purified by crystallising out from ligroin.
Benzoyltetramethyl-y-oxypiperidine carboacid methylester is very easily soluble
in alcohol, ether, chloroform and benzol. It crystallises out of hot ligroin in
fine colourless prisms which melt at about 91-92° C.
The base combines with inorganic and organic acids to form neutral reacting
salts.
The nitric, nitrous, bydrochloric, bromic, iodic, sulphuric, boric, phosphoric,
double carbonic, formic, acetic, citric, tartaric, succinic, salicylic, tropic, atropic,
benzoic, lactic and malic acid salts have been produced. With the exception of the
formic acid salt, which dissolves in four parts of water and forms large shining
crystals, all these salts are very difficultly soluble in cold water.
PRODUCTION OF HOMOLOGOUS ESTERS OF TETRAMETHYL-Y-OXYPIPERIDINE-
CARBO ACID.
If in place of methylalcohol, its homologues (ethyl, propyl alcohol and the like,
react upon tetramethyl-y-oxypiperidinecarboacid as described under A II, the
hydrochloric acid salt of the homologues of tetramethyl-y-oxypiperidinecarboacid
methylester are produced as colourless easily soluble crystalline masses..
The free tetramethyl-y-oxypiperidinecarboacid ethylester
HO-C-COOC2H
CH2
H₂C
:
CH³ C
CH3
CH3
CH3
NH
forms like the corresponding methylester large compact crystals of melting point
about 96-97° C.; it is as easily as this latter saponified by water.
In the same way as the tetramethyl-y-oxypiperidine carboacid methylester the
other alkylesters also can be transformed into benzoyl-derivatives which in their
properties as also in respect of the solubility of their salts are closely related to
the corresponding methyl compound.
Benzoyltetramethyl-y-oxypiperidinecarboacid ethylester

page_text: The n-alkyl-benzoyltetramethyl-y-oxypiperidine-carboacid esters having equal
alkyl groups in the carboxyl and imide may be produced not only in the way
herein before described but also by causing alkalihydrate and alkyl halide to react
upon an alcoholic solution of a salt of benzoyltetramethyl-y-oxypiperidine carbo-
acid or the free acid.
The formation of the n-methylbenzoyl-y-oxypiperidine carboacid methylester,
for example takes place according to the equation
:-

page_text: (B.) PRODUCTion of BenzoYLDIMETHYLPHENYL-y-OXYPIPERIDINE CARBO-
ACID METHYLESTER FROM BENZALDIACETONAMINE.
I. PRODUCTION OF DIMETHYLPHENYL-y-OXYPIPERIDINE CARBOacid.
On 055 kg. of powdered potassium cyanido there is poured a solution in
ether of 1 kg. benzaldiacetonamine (Annalen der Chemie 193 page 62 and
Ber. d. Deutschen Chem. Ges. 16 page 2236) and 1,3 kg. of a concentrated
solution in water of hydrochloric acid is gradually added to the mixture, stirring
and cooling with ice at the same time. The ether is then distilled off, and the
cyanhydrin formed saponified by boiling the residuum with concentrated hydro-
chloric acid for several hours.
The excess of hydrochloric acid is evaporated on the water bath, the residuum is
dissolved in dilute caustic soda solution and mixed whilst hot with acetic acid.
Dimethylphenyl-y-oxypiperidine carboacid separates out as a colourless crystalline
precipitate, which is filtered, washed and dried.
"
Dimethylphenyl-y-oxypiperidinecarboacid is almost insoluble in water, alcohol
and ether, alkaline carbonates, ammonia and dilute acetic acid; it is very easily
soluble in dilute mineral acids. It melts at about 250-270° C. with decomposition.
The foregoing reactions are shown by the following equations:-

page_text: is evolved. The melt, is poured into ice water, shaken up repeatedly with ether
to remove the excess of benzoylchloride, the solution deprived of the ether is
precipitated with caustic soda solution and the deposited base taken up with ether.
After distilling off the ether benzoyldimethylphenyl-y-oxypiperidinecarboacid
methylester
The production of benzoyltrimethyl-y-oxypiperidine carboacid methylester
CsHgC00C-C00CH,
H2C
CH2
CH3>C
CH-CH₂
CH3
NH
from vinyldiacetonamine
có
H₂C
CH2
CH3>C
CH-CH3
CH3
NH
takes place in an analogous manner, to that described under A and B. The melting
point of the ester is about 100° C. The trimethyl-y-oxypiperidine carboacid is a
colourless crystalline body, having the same properties as the hereinbefore described
y-oxypiperidine-carboacids. It melts at high temperature with decomposition.
The homologous esters may of course also be produced from the benzoyl com-
pounds named in B and C. Likewise the n-alkyl derivatives from the benzoyl
compounds named in B and C can be obtained in the same ways as the analogous
compounds derived from triacetonamine.
n-methyl benzoyl-dimethylphenyl-y-oxypiperidinecarboacid methylester

page_text: crystallizes from ligroin in star like needles melting point at about 101° C.
The toluyl-y-oxypiperidine carboacid esters, and n-alkyl-toluyl-y-oxypiperidine
carboacid esters may be obtained in the same ways as the corresponding benzoyl
compounds if instead of substituting the benzoyl group for the hydrogen in the
hydroxyl the hydrogen is replaced with ortho- or meta- or paratoluyl.
The toluyl-y-oxypiperidine carboacid esters and n-alkyl-toluyl-y-oxypiperidine
carboacid-esters are colourless, crystalline bodies which are insoluble in water and
caustic alkalies, but soluble in mineral acids, ether, ligroin.
The toluyl-y-oxypiperidine carbo acids are obtained in a similar manner as the
benzoyltetramethyl-y-oxypiperidine-carboacid, and also from.colourless crystalline
bodies.
n-methyl-o-toluyltetramethyl-y-oxypiperidine carboacid methylester
Having now particularly described and ascertained the nature of my said inven- 20
tion and in what manner the same is to be performed I declare that what I
claim is :-

page_text: then saponifying the nitrile produced to a y-piperidine carboacid. Also producing
benzoylated and toluylated alkyl esters from the said y-oxypiperidinecarboacids
substantially as described.
2. The production of benzoyl-y-oxypiperidine carboacid esters and n-alkyl-
benzoyl-y-oxypiperidine carboacid esters as well as the corresponding toluyl
compounds by linking hydrocyanic acid to triacetonamine and analogous derivatives
as benzaldiacetonamine and vinyldiacetonamine saponifying the nitrile so produced
to y-oxypiperidine carbo-acid and transforming the latter into ester and into com-
pounds of the ester by replacing the hydrogen atom of hydroxyl with benzoyl or
toluyl (o.m.n) and the hydrogen atom of imide by alcoholic radicals.
3. The modification of the process described in Claim 2, for the production of
n-alkyl-benzoyl-y-oxypiperidine carboacid esters and n-alkyl-toluyl-y-oxypiperidine
carbo-acid esters having equal alkyl groups in the carboxyl and imide by first
benzoylating or toluylating the y-oxypiperidine carboacids derived from triaceton-
amine and its analogous derivatives and alkylising and esterifying the acidyl
compound or a salt of the same.
4. As new products the hereindescribed y-oxypiperidine carboacids.
5. As new products the herein described benzoyl-y-oxypiperidinecarboacid esters
and n-alkylbenzoyl-y-oxypiperidineacid esters and their salts, as well as the described
toluyl-y-oxypiperidinecarboacid esters and n-alkyl toluyl-y-oxypiperidinecarboacid
esters.
Dated thin 27th
1000