PIPERAZINE DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF

DERIVES DE LA PIPERAZINE ET PROCEDE POUR SA PREPARATION

English Abstract

PIPERAZINE DERIVATIVES AND PROCESS FOR THE PREPARATION
THEREOF
A b s t r a c t
the invention relates to a new and improved
process for the preparation of 8-{4- [ 4-(2-pyrimidinyl)-
-l-piperazinyl]-butyl}-8-aza-spiro[ 4.5]decane-7,9-
-dione of the Formula I
<IMG> (I)
and pharmaceutically acceptable acid addition salts
thereof, which comprises hydrogenating a compound of
the general Formula II
<IMG> (II)
(wherein A stands for -C?C- or -CH=CH-) and, if desired,
converting the compound of the Formula I thus obtained
into a pharmaceutically acceptable acid addition salt
thereof.

The compound of the Formula I is a known
anxioselective agent.
The invention also relates to inter-
mediates used in the above process and a method for
the preparation thereof.

Claims

-25- 23305-1122
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process preparing a 8-{4-[4-(2-pyrimidinyl)-1-
piperazinyl]-butyl}-8-aza-spiro[4,5]decane-7,9-dione of the
Formula I
<IMG> (I)
or a pharmaceutically acceptable acid addition salt thereof,
which comprises hydrogenating a compound of the general
Formula II
<IMG> (II)
(wherein A stands for -C?C- or -CH=CH-) and if required, con-
verting the compound of the Formula I thus obtained into a
pharmaceutically acceptable acid addition salt thereof.
2. Process according to Claim 1, which comprises
hydrogenating the compound of the Formula IIA

-26- 23305-1122
<IMG> (IIA)
3. Process according to Claim 1, which comprises hydro-
genating the compound of the Formula IIB
<IMG> (IIB)
4. Process according to Claim 2 which comprises hydro-
genating the compound of the Formula IIA in the presence of a
metal catalyst.
5. Process according to Claim 4, which comprises using
a palladium or Raney-nickel catalyst.
6. Process according to Claim 5, which comprises
carrying out hydrogenation under atmospheric pressure at room
temperature.
7. Process according to Claim 6, which comprises
carrying out hydrogenation in the presence of an inert organic

-27- 23305-1122
solvent.
8. Process according to Claim 7, which comprises using
a lower aliphatic alcohol as inert organic solvent.
9. Process according to Claim 3, which comprises
hydrogenating the compound of the general Formula IIB in the
presence of a metal catalyst.
10. Process according to Claim 9, which comprises
using a palladium catalyst.
11. A compound of the general Formula II
<IMG> (II)
wherein A stands for -C?C- or -CH=CH- or an acid addition
salt thereof.
12. A compound of the Formula IIA
<IMG> (IIA)

-28- 23305-1122
or an acid addition thereof.
13. A compund of the Formula IIB
<IMG> (IIB)
or an acid addition salt thereof.
14. Process preparing a compound of the general
Formula II (wherein A stands for -C?C-or -CH=CH-) as defined in
claim 11 or an acid addition salt thereof, which comprises
a) for the preparation of a compound of the Formula II
wherein A stands for -C?C- subjecting the propine
derivative of the Formula III
<IMG> (III)
to Mannich condensation with an amine of the Formula
IV;
<IMG> (IV)

-29- 23305-1122
or
b) for the preparation of a compound of Formula II
wherein A stands for -C?C- reacting the propine
derivative of the Formula III as defined above, with
an alkyl magnesium halide of the general Formula V
R-Mg-Hlg (V)
(wherein R stands for C1-4 alkyl and Hlg is chlorine,
iodine or bromine), reacting the compound of the
general Formula VI
<IMG> (VI)
thus obtained (wherein Hlg is as stated above) with
at least one molar equivalent amount of trioxymethyl-
ene or formaldehyde, converting the substituted amino
alcohol of the Formula VII thus obtained
<IMG> (VII)
into a reactive ester of the general Formula VIII

-30- 23305-1122
<IMG> (VIII)
(wherein X stands for a reactive ester group) and
reacting the compound of the general Formula VIII thus
obtained with a piperazine derivative of the Formula
IV; or
c) for the preparation of the compound of the Formula II
wherein A stands for -CH=CH- subjecting a compound of
the Formula II wherein A stands for -C?C- to partial
hydrogenation;
and if required, converting a compound of the general Formula
II thus obtained into an acid addition salt thereof or setting
free the same from an acid addition salt.
15. Process according to method a) of Claim 14, which
comprises carrying out Mannich condensation by using parafor-
maldehyde.
16. Process according to Claim 15, which comprises
carrying out the reaction under heating.
17. Process according to any one of Claim 14 method a),
15 and 16, which comprises carrying out the reaction in an inert

-31- 23305-1122
organic solvent.
18. Process according to method b) of Claim 14, which
comprises using as alkyl magnesium halide of the general Formula
V methyl magnesium iodide, methyl magnesium bromide, methyl
magnesium chloride, ethyl magnesium iodide, ethyl magnesium
chloride or ethyl magnesium bromide.
19. Process according to Claim 18, which comprises
carrying out the reaction of the compounds of the Formulae III
and V in ethereal medium under heating.
20. Process according to method b) of Claim 14, which
comprises reacting the compound of the general Formula VI with
trioxymethylene or gaseous formaldehyde under heating.
21. Process according to Claim 20, which comprises
using trioxymethylene or formaldehyde in an amount of 1 - 1.1
moles related to 1 mole of the compound of the general
Formula VI.
22. Process according to method b) of Claim 14, which
comprises converting a compound of the Formula VII into an ester
of the general Formula VIII, wherein X stands for halogen,
alkylsulfonyloxy or arylsulfonyloxy.
23. Process according to Claim 22, which comprises
preparing an ester of the general Formula VIII wherein X stands

-32- 23305-1122
for chlorine, bromine, iodine, methanesulphonyloxy, phenyl-
sulfonyloxy, p-bromo-phenylsulfonyloxy of p-toluenesulphonyl-
oxy.
24. Process according to Claim 22 or 23, which com-
prises reacting the compound of the Formula VII with p-toluene-
solfonyl chloride.
25. Process according to method b) of Claim 14, which
comprises reacting a compound of the general Formula VIII with
the piperazine derivative of the general Formula IV in an
inert organic solvent.
26. Process according to method c) of Claim 14, which
comprises hydrogenating the compound of the Formula II wherein
A stands for -C?C- with hydrogen in the presence of a poisoned
catalyst to the compound of the Formula II wherein A stands for
-CH=CH-.
27. Process according to Claim 26, which comprises
using a palladium catalyst poisoned with quinoline, calcium
carbonate or lead acetate.
28. Process according to Claim 26 or 27, which com-
prises carrying out partial hydrogenation at room temperature
under atmospheric pressure.
29. Process according to Claim 26 or 27, which

-33- 23305-1122
comprises carryinq out partial hydrogenation in a lower ali-
phatic alcohol as medium.
30. A pharmaceutical composition comprising as active
ingredient a compound of the general Formula II
<IMG> (II)
(wherein A stand for -C?C- or -CH=CH-) or a pharmaceutically
acceptable acid addition salt thereof in admixture with suitable
inert pharmaceutical carriers.

Description

~3001~
PIPERAZINE DERIVATIV:ES AND PRO~ESS FOR ~HE PREPARA~IOI~
'rHER~O~
nlhis invention relates to a new and
improved process for the preparation of pharmaceutical-
ly active piperazine derivatives and to new inter-
mediates useful in the preparation thereof and also
to a process for the preparation of the said intermediates.
According to an aspect of the present invention
lo there is provided a pro~ess for the preparation of the
therapeutically active known 8-{ 4-/ 4-(2-pyrimidinyl) -1-
-piperazlnyl7-butyl~-8-aza-1-spiro/ 4057-decane-7,9-
-dione of the Formula Io
X~`l (CH;~)4 N~ N~
It is known that the 8-{ 4-1 4-(2-pyrimidinyl)-
-1-piperazinyl7-butyl} -8-aza-spiror4..~7decane-799-dione
of the ~ormula I possesses valuable anxioselective
properties (Ug Patent ~o. 1,332,194)~, In prior art
several methods are disclosed for the preparation of the
compound of the ~ormula Io
A 4123-52 P~
-

1300141
-- 2 --
According to UK patent No. 1,332,194 the
compound OI the ~ormula I is pre~ared by reacting
8-oxa spiro/ 4.~7decane-7,~-dione with 1-(4-aminobut-Jl)-
-1-(2'-pyrimidinyl)-~iperazine. The reaction is
accomplished in pJridine at the boiling point of the
reaction mi~tvre. The desired compound of the Formula I
is obtained in crude form with medium yield. ~he crude
product is purified in the free base form by crystalliza-
tion or fractional distillation in vacuo, The drawback
of the above first purification method is that the
lossess are significant while fractional distillation
in vacuo is carried out at high tem~erature (2ao-265 C)
under lOW pressure (13.3 Pa), which constitutes a severe
thermal load and leads to decomposition of the product.
According to an other method disclosed in
UE patent No. 1,332,194 8-(4-chlorobutyl)-8-aza-spiro-
r 4.~ decane-7,9-dione is reacted with N-(2-pyrimidin~
-piperazine in the presence of sodium carbonate in n-
-butanol at the boiling point of the reaction mixture
for 3 days. ~he ertremely long reaction time makes the
process unsuitable for economical industrial scale
manufacture. A further disadvantage is that the product
can be purified but with tne aid of complicated and
circumstantial methods. A still further drawback resides
in the fact that the 1-bromo-4-chloro-butane used as
starting material in the prepara-tion of 8-t4-chloro-
butyl)-8-aza-spirol 4.~ decane-7,9-dione is a~very
difficultly available compound, which can be prepared

~30~)141
only by means of complicated methods.
According to a still further process
disclosed in UX patent ~o. 1,332,194 8-oxa-spiror 4.57-
decane-799-dione is first converted into 8-aza-spiro-
f 4.57decane-7,9-dione. The 1-(4-chlorobutyl)-4-(2-
-pyrimidinyl) - piperazine prepared from N-(2-pyrimidinyl)-
-piperazine and l-bromo-4-chloro-butane is reacted with
8-aza-spiror 4,~ decane-7~9-dione. This process comprises
se~eral steps which are very delicate and can be carried
o out only under serious difficulties. ~he compound of
the Formula I thus obtained is suitable for pharmaceutical
purposes only af-ter severalfold purification. A further
drawback resides in the difficult availability of the
l-bromo-4-chloro-butane used as starting material.
~he 1-(4-aminobutyl)-4 (2-pyrimidinyl)-
-piperazine can be prepared by reacting 1-(2-pyrimidinyl)-
-piperazine with 3-chloropropionitrile in n-butanol
as medium at the boiling point of the reaction mixture
for a longer period of time (the reaction time is 16
hours). ~he intermediate thus obtained must be subjected
to purification by crystallization (yield 70 %). ~he
intermediate nitrile is catalytically hydrogenated under
pressure with a yield of about 70 % ~UK patent No.
1, 332,'1g4) .
In Hungarian patent No. 187,999 a further
process is set forth. ~he compound of the ~ormula I is
prepared as follows: from 1-t4-c~obutyl)-4-t2-
-pyrimidinyl)-piperazine first the spiro quaternary

_4_ ~3~14i 23305-1122
ammonium piperazine derivative of the Formula IX
C N ~ N ~ O~ X~ (IX)
is prepared which is reacted with 8-aza-spiro [4,5]-decane-7,9-
dione in the presence of a strong base. This process is accom-
panied by a number of drawbacks. Thus the yield is low, the
synthesis is a multistep process and the contaminated product
obtained can be only difficultly purified.
According to Swiss patent No~ 647,518 8-aza-spiro
[4,5]decane-7,9-dione is first reacted with 1,4-dibromo-butane,
the 4-bromo-butyl derivative thus obtained is treated with
piperazine, whereupon the product thus obtained is reacted with
2-chloro-pyrimidine. The object of this process is to prepare
a compound labelled with C isotope and is therefore but of
theoretical importance.
According to Spanish patent No. 536,286 the potassium
salt of 8-aza-spiro [4,5]decane-7,9-dione is reacted with 4-
chloro-butyraldehyde, whereupon the product thus obtained is
reacted with N-(2-pyrimidinyl)-piperazine under reductive con-
ditions. This process is of mere academical significance too
and is unsuitable for industrial scale manufacture~
The present invention seeks to provide a process
which overcomes the drawbacks

~300~41
of the above known methods and enables t~e favourable
preparation of the compound of the ~ormula I on
industrial scale too by using readily available start-
ing materials. It is a further object of the present
invention to provide a process which gives the desired
compound of the Formula I with good yields and in high
purity.
According to the present invention there
is provided a process for the preparation of 8-{4-r 4-(2-
-pyrimidinyl)-l-piperazinyl7-butyl~-8-aza-spiror 4. ~ -
decane-7,9-dione of the Formula I and pharmaceutically
acceptable acid addition salts thereo~ which comprises
hvdrogenating a compound of the general Formula II
~ -CH2-A-CH2-N~ N ~ ~ (II)
~wherein A stands for -C-C- or -CH=CH-3 and, if desired,
converting the compound of the Formula I thus obtained
into a pharmaceutically acceptable acid addition salt
thereof.
According to a form of realization of the
process of the present invention the compound of the
Formula IIA is hydrogenated. ~he reaction may be
performed in the presence of a metal catalyst with
hydrogen. AS catalyst preferably palladium or Raney-
-nickel can be used. One may particularly advantageously
, , . , ~

~3~01
-- 6 --
proceed by carrying out hydrogenation in the presence
of a palladium catalyst applied onto a charcoal carrier.
Hydrogenation of the compound of the Formula IIA
~ 'Cl~2-c-c-c~2-N ~ N ~ N ~ (II~)
can be accomplished in an inert organic solventO As
reaction medium preferably lower ali;ohatic alcohols
- particularly methanol or ethanol - can be usedO
Hydrogenation may be carried out preferably under
atmospheric pressure at room temperatureO
~he compound of ~ormula I can be isola~ed
from the reaction mixture by known methods. Ihus one
may proceed by removing the catalyst by filtration and
evaporating the filtrateu ~he catalyst can be re-
-introduced into the hydrogenation cycle directly
without further treatment.
Ihe compound of the Formula I thus obtained
is of high purity and is suitable for pharmaceutical
use wit'nout any special purificationO
According to an other form of reali.zation
of the process of the present invention the compound
o~ the ~ormula IIB

_ 7_ ~30~i41
,~ ~\ N
~ N-C ~ CH=CH-~H2-N~ N ~ O ~ (IIB)
is reduced. ~he reaction cen oe performed by catalytic
hydrogenation. As metal catalyst preferably palladium
can be used. ~he reaction may be carried out in an inert
organic solvert. As reaction medium preferably lower
lo aliphatic alcohols - particularly methanol or ethanol -
can be used. Hydrogenation of the compound of ~he
~ormula II~ can be accomplished preferably under
atmospheric pressure at room temperature.
~he compound of the ~ormula I thus obtained
can be converted into an acid addition saIt thereof by
known methods. Any pharmaceutically suitable inorganic
acid (e.g~ hydrochloric acid, hydrogen bromide, sulfuric
acid, nitric acid etcO) or organic acid (eOg. maleic
acid, fumaric acid, lactic acid, malic acid, tartaric acid,
succinic acid etc.) can be used.
~ he starting materials of the general ~o^mula II
are new compounds.
According to a further aspect of the present
invention there are provided new compounds of the general
~ormula II (wherein A stands for -C-C- or -CH=CH-) .
~ hus the following new compounds are provided:
8-~4-/ 4-(2-pyrimidinyl)-1-pipera~inyl7-but-2-inyl}-8-
-aza-spiror 4.57decane-7,9-dione of the ~ormula IIA;

~ 8 - 13 O O 1 4 1
8-{4-~ 4-(2-pJrimidinil)-l-piperazin~ ~ -butene-2-yl}-8-
-aza-spirol 4.57decane-7,9-dione of the ~ormula IIB.
~ he compounds o~ the general Formula II
are,on the one handtuseful intermediates suitable
for the preparation of the therapeutically active
known compound of the ~o~ .la I while,on the other hand,
possess valuable pharmaceutical properties per se.
According to a further feature of the
present invention there are provided pharmaceutical
lo compositions comprising as active ingredient a compound
of the general Formula II (wherein A is as stated above)
or a pharmaceutically acceptable acid addition salt
thereof in admixture with suitable inert carriers.
~he pharmaceutical compositions o~ the
present invention can be prepared by known methods of
pharmaceutical industry and contain eonventional
pharmaceutical carriers and auxiliary agents.
According to a still ~urther feature of
the present invention there is provided a process or
the preparation of compounds of the general Formula II
(wherein A stands for -C-C- or -CH=CH-) and aeid
addition salts thereo~ which comprises
a) for the preparation of the eompound
of the Formula IIA, subjeeting the pro ine derivative
of the ~ormula III
.. . _ _ . _ _ _ . . . . _ . . . . _ _ _ _ . _ _ _ . . _ .. . . ..

13001A~ .
_ g _ ,
~N C~-C-Ch (III)
to Mannich condensation with an amine of the ~ormula IV;
~~~~ N~ ~IVJ
HN~N~
or
b) for the preparation of the compound
of the ~ormula IIA, reacting the propine derivative
of the ~o~mula III with an alkyl magnesium halide of
the general ~ormula V
R-Mg-Hlg (V)
(wherein R stands for ~1-4 alkyl and Hlg is chlorine,
iodine or bromine), reacting the compound of the
general ~ormula VI
/p ~VI)
CX~N-CH2-C~ M9-Hl9
O
_ .. ~ . _ . . . .

1o l300141
thus obtained (wherein Hlg is as stated above)
with at least one molar equivalent amount of tri-
oxymethylene or formaldehyde, converting the substitut-
ed amino alcohol of the ~ormula VII
(VII)
CH2- C-C- CH2-OH
lo into a reactive ester of the general Formula VIII
- tVIII)
~-CH2-C_C-CH2 X

(wherein X stands for a reactive ester group) and
reacting the compound of the general ~ormula VIII
thus obtained with a piperazine derivative of the0 ~o;^mula IV; or
c) for the preparation of the compound
of the Formula II3, subjecting the compound of the
Formula IIA to partial hydrogenation,
and, if desired9 converting a compound of the general
Formula II thus obtained into an acid addition salt
thereof or setting free thebase from an acid addition
saltO

31~A~
According to method a) the compound of the
Formula IIA is prepared by sub~ecting the propine
derivative of the ~o mula III to Mannich condensation
with an amine of the Formula IV. ~he Mannich condensation
is carried out by methods known per se r Calvin A.
~uehler, Donald E. Pearson: Survey of Organic Syntheses
(USA 1970) Vol. l, page 4657. One may proceed preferably
be using formaldehyde in the form of paraformaldehyde.
The reaction may be accomplished preferably under heating,
particularly at the boiling point of the reaction mixture.
The reaction may be carried out in an inert organic
solvent. ~s reaction meaium preferably an ether (e.g.
diethyl ether, dioxane or tetrahydrofurane) c~ be used,
From the reaction mixture the compound of the Formula IIA
can be isolated in a known manner (e.g. by extraction
with a suitable organic solvent)~
In the first step of method b) the propine
derivative of the ~ormula III is reacted with an alkyl
magnesium halide of the general Formula V. R stands for
a straight or branched chain alkyl group having 1-4 carbon
atoms (e.g. methyl,,~ ethyl, n-propyl, isobutyl etc.).
As compound of the general Formula V preferably methyl
magnesium iodide, methyl magnesium bromide, methyl
magnesium chloride, e-th-yl magnesium iodide, ethyl
; 25 magnesium chloride or ethyl magnesium bromide can be used.
The reaction of the compounds of the general Formula III
and V can be accomplished preferably in anhydrous ethereal
medium under heating,
_ _ _ _ _ _ _ _ _ _ _ _ . . . _

- 12 - 130014i
The compound of the general Formula VI
thus obtained is reacted - preferably without isolation -
with at least a molar equivalent amount of trioxy-
methylene or araformaldehyde. It is preferred to
use gaseous formaldehyde. ~he trioxymethylene or form-
alc.ehyde is preferably used in an amount of 1 - 1.1
moles - particularly 1.0 - 1.05 moles - related to
1 mole of the con~pound of the general Formul~ VI,
~he reaction may be carried out preferably under heat-
ing. ~he compound of the general Formula VII can beisolated by evaporating the e~heral solution.
~ he compound of the ~ormula VII thus
obtained is converted into an ester of the general
Formula VIII by methods known per se. X stands prefer-
ably for halogen (e.g. chlorine, bromine or iodine),alkylsulfonyloxy (e.gO methanesulfonyloxy) or aryl-
sulfonyloxy ~e.g. phenylsulfonyloxy, ~-bromophenyl-
sulfonyloxy,' ~-toluene-sulfon~yloxy etc~). One may
preferably proceed by reacting the compound of the
Formula VII with ~-toluene-sulfonyl chloride. ~he
reaction may be càrried out at room temperature
or under slight warming.
~ he compound of the general Formula VIII
t~us obt~ined is reacted - without or after isolation,
preferably directly without isolation - with a
piperazine derivative of the general Formula IV~ ~he
reaction may be accomplished in a manner known per se.
~he reaction may be preferably carried out in an

l ~ i30~141
inert organic solvent. ~s reaction medium e.g.
aromatic hydrocarbons (e.g. benzene, toluene, xylene
etc.) c~n be used. ~he reaction may be preferably
perormed under heating, particularly at the boiling
point o the reaction mixture.
~ he compound of the general ~ormula IIA
thus obtained can be isolated in a manner known per
se (e.g. by evaporating the reaction mixture).
According to method c) the compound o
lo the ~ormula IIB is prepared by subjecting the compound
of the Formula IIA to partial hydrogenation. Reduction
is carried out by catalytic hydrogenation, preferably
in the presence of a poisoned metal catalyst. One
may preferably proceed by USillg a palladium catalyst
poisoned by quinoline, calcium carbonate or lead
acetate. It is particularly advantageous to use a
catalyst poisoned by auinoline r Org. Synth. Coll.
Vol. 3, 629 ~1955) 7. Partial hydrogenation may be
preferably carried out at room temperature under
atmospheric pressure. ~he reaction may be preferably
accomplished in the presence of an inert organic
solvent. As reaction medium advantageously a lower
aliphatic alcohol (e.g. methanol or ethanol) may be
used. ~he compound of the ~ormula IIB thus obtained
can be isolated by known methods (eOg. by filtering
the catalyst and evaporating the filtrate)O
~ he compound of the general ~ormula II can
be converted into an acid addition salt thereo by

130014
-- 14 --
methods kno~n per se. ~or salt formation preferably
pharmaceutically acceptable inorganic or organic acids
can be used (e.g. hydrochloric acid, hydrogen bromide,
sulfuric acid,' nitric acid, or maleic acid, fumaric
acid, lactic acid, malic acid, tartaric acid, succinic
acid etc.). Salt formation may be advantageously
performed by reacting t'ne free base of the general
~ormula II with a molar ~uivalent amount of the correspond-
ing acid in an inert organic solvent.
lo The compound of the general ~ormula II can
be set free from an acid addition salt thereof in a
manner known per se by treating with a suitable base.
The 8-aza-spiro/ 4. ~ decane-7,9-dione-8-
~prop-2-ine of the ~ormula III used as starting material
in the above procedures is a known compound.
According to a still further aspect Of
the present invention there is provided a process for
the preparation of 8-aza-spiror 4. ~ decane-7,9-dione-
-8-prop-2-ine of the ~ormula III ~hich comprises
reacting 8-aza-spiror 4~ ~ decane-779-dione of the
~ormula X
(X)

`` ~3~41
-- 15 --
with a propargyl halide of the general ~ormula XI
Hal-CH2-~-~H ! ~XI)
(wherein Hal stands for bromine~ chlorine or iodine)
in an inert solvent, in the presence of an acid bind-
ing agent.
It is known that the 8-aza-spiror 4. ~ -
decane-7,9-dione-8-prop-2-ine of the Formula III can
be prepared by heating a mi~ture of 8-o~a-spiro/~4.57-
decane-7,9-dione and propargyl amine in pyridine to
boiling for 15 hours, evaporating the dilute reaction
mixture and purifying the residue by distillation in
vacuo r yao-Gua Wu et al: J. Med. Chem. 12, 876-881
(1~69) 7. The compound of the ~ormula III is obtained
with a yield of 76 %.
The above process is accompanied by several
drawbacks which are particularly serious on industrial
scale manufacture. The reaction time is very ~ong (15
hours) and the temperature used is high (above 115 C).
The specific utilization of the volume of the reactor
is unfavourable. The treatment,recovery and elimination
of the pyridine used as solvent is problematic and
comprises serious hazards of environmental pollution.
A further disadvantage resides in the fact that propargyl
amine used as starting material is a difficultly available
expensive substance.
It is a further object of the

- 16- 1300~4~
present invention to overcome the above drawbacks
of the known procedures and to elaborate an economical
process fo~ the p~-:eparatiol oî ~ne compo~J~(i of the
Formula III which is favourably leasible on industrial
scale as well.
~ he present invention is based on the
recognition that on reacting 8-aza-spiror 4.57decane-
-7;9-dione of the ~ormula X with a propargyl halide
of the ~ormula XI the compoulld of the ~ormula III
is obtained with good yields and in high purity in
a readily feasible simple manner.
As compound of the general ~ormula XI
preferably propargyl bromide may be usedO
~ e starting materials of the ~ormulae X
and XI can be used in equimolar amountsbut the prop æ gyl
halide of the general ~ormula XI can be applied in a
small - 10-20 molar % - excess as well.
~ he reaction can be c æ ried out in any
suitable inert organic solvent. As reaction medium
a~y organic solvent can be used ~hich does not enter
into reaction with the components and does not
influence the reaction in an adverse manner, It is
preferred to use an ether (e~g. tetrahydrofurane,
dioxane etc.),; ester (e.gO ethyl acetate), nitrile
(e.g. acetonitrile) or ketone (eO~0 acetone or methyl
ethyl ketone) or a mixture ~hereof as reaction mediumO
~ he reaction is carried out in the presence
of ~n acid binding agent. Yor this purpose preferably

1300~4
-- 17 --
an alkali c~rbonate (particularly sodium or potassium
carbonate) can be used but other inorganic bases
can be applled as well, eOg. an ~lkaline earth metal
carbonate ~e.g. c~lcium carbonate), an alkali hydrogen
carbonate (e.g. sodium or potassium hydrogen carbonate),
an alkali hydride (e.g. sodium hydride) or alkali
amide ~e~g. sodium amide etc.). ~urthermore,tertiary
organic bases can also be used as acid binding agent
(e.g. trialkyl amines,' such as triethyl amine).
The reaction temperature can vary between
wide ranges. ~hus one may generally work at 45-110 C,
preferably at 55-100 C. ~he reaction temperature
depends on the solvent used.
The reaction takes place very rapidly,' the
reaction time amounts to a few hours.
The reaction mixture can be worked up in a
very simple manner. ~hus,one may proceed by c~oling
the reaction mixture,' removing the insoluble substances
(alkali carbonate,i alkali halide) by filtration or
centrifuging and evaporating the filtrate. ~hus,the
compound of the Formula III is obtained in hi~hly pure
form ~;lhich can be used for the further reactions direct-
ly without further purification. ~he sample of analytic
purity of the product is obtained by fractional distilla-
tion in vacuo.
~ he advantages of the above process of thepresent invention can be summarized as follows:
- no long reaction time is required,'
. . _ . . .. . . .

- 18 - ~30~4~
- the reaction can be accomplishQd at a temperature
not exceeding 100 C,I
- no pyridine is used and therefore the difficulties
~hich accompany the recovery and elimination of
this solvent are overcome,!
- the process is more favourable to the environment,
- the process is readily feasible on industrial scale,
too,
- the specific utilization of the apparatus is favourable;
lo - the yield is very high,
- the desired compound of the Formula III is obtained
in highly pure form and can be used for the further
reaction directly,without further purification.
Further details of the process are to be
found in the following Examples without limiting the
scope of protection to the said Examples.
Pre~aration of t~Lcom~oun~ of Formula I
Exam-ple'l' ' ' ' ' ''
8-14-/ 4-(2-Pyrimidinyl)-l-piperazin~17-
-~utyl~-8-aza-spiro/ 4,57decane-7,~-dione
~o'a'solution'of'38.I5 g''CO.l'mole)'of''
8-[4-/ 4-(2-pyrimidinyl)-1 piperazinyl7-but-2-in-yl}-
-8-aza-spiror 4.~7decane-7,9-dione in 150 ml of ethanol
1 g of a pall-adiium/charcoal catalyst is added, where-
upon the mixture is hydrogenated under atmospheric
pressure at room temperature ~nder vigorous stirring
until the hydrogen consumption stops (2 equivalents of
hydrogen,l about 5 litres). ~he catalyst is removed by
~ ~ ~ . _ . . _ _ _ _ _ , _ . . _ _ . . . , . _ . . . . . .

- lg 1300~41
filtration and can be directl~ used in t~e next
hydrogenation step. ~he filtrate is evaporated in
~acuo. ~hus 36.85 g of the desired compound are obtained,
yield 95.6 %. M~po 91-99 C tthe melting point
disclosed in prior art amcunts ~o 90-98 C).
Anal~-sis for the ~ormula C21H31N502 (385~52)
c~lc.: C % = 65043; H /0 = 8.11; ~T % = 18.17;
fovnd: C % = 65.01, H % = 3.0Q, ~T % = 18015,
~he abo-~e base is converted into the hydro-
chloride by reacting wi~ an equimolar amount of
hydrogen chloride in ethanol~ l'he hydrochloride melts
at 200-202 C (the mel~ing point disclosed in prior
art amounts to 201.5 - 202.5 C)O
Lnalysis for the ~ormula C21H31CliT502oXC1 ~421098)
calc.: C % = 59.77, ~ % = 7.~5, ~T % = 4.3, Cl %= 8.40;
found: C % = 59.51;! H ~ = 7.50, N % = 4.26, Cl %= 8037.
Preparation of the com_oun~ of the
~ormuIa IIA
xample 2
8-~4-/4-(2-Pyrimidinyl)-l-piPerazin~l7-but-
-Z-in-~I~-8-aza-spiro! 4057aecane-7 ~-dione
Into a 250 ml round-bottomed flask equipped
with a stirrer ~ld reflux condenser 20.5 g (ol mole)
f 8-aza-spiror 4057decane-7 9-dione-8-prop-2-ine
25 ml of dioxane, I7.2 g (0~105 mole) of 1-(2-
-p~-rimidinyl)-piperazine, 3.6 g of paraformalidehyde and
0.2 ~ of cupri-(II)acetaJe a~e introduced. ~e reaction

- 20 - i30~4~
mixture is heated to boiling for 3 hours~ cooled to
room temperature, poured into water and extracted
three times with 50 ml of benzene each. ~he united
benzene solutions are clarified with activated charcoal
and evaporated on a hot water-bath. ~hus 33 95 g of the
desired compound are obtained, yield 89 /c, m.p.:
78-80 C (petrolet'her)O
Analysis for the formula C21~27~502 (381.49)
calc.: C % = 66.12; H % = 7.13; N % = 18.36;
lo found: C % = 66.02; H ,h = 7.22; N % = 18.30
Example 3
~4-L 4-(2-p~rimidin~l~-1-piperazinyl7-but-
-2-in-y ~-8-aza-spiro/ 4.5Zdecane-7,9-dione
. A Grignard compound is'prepared from 15 6'g
(0.11 mole) of methyl iodide and 2.68 g (0~11 g-atom)
of magnesium in 170 ml of anhyd-rous ether,whereupon
a solution of 20.5 g (0.1 mole) of 8-aza~spiror 4. ~ -
decane-7,9-dione-8-prop-2-ine and 50 ml of anhydrous
ether is added dropwise under vigorous stirring~ ~he
reaction mixture is heated to boiling until the develop-
ment of methane gas comes to an end, whereupon 3 g
(0.1 mole) of trioxymethylene (or 0.1 mole of anhydrous
gaseous fromaldehyde) are added. ~he reaction mixture
is heated to boiling for a further period of 4 hours
and thereafter poured into a solution of 10 g of
ammonium chloride and 35 ml of icecold water. ~he
etheral solution is spearated, dried over anhydrous

- 21 - i30~4~
magnesium sulfate and evaporated.
The oily residue (2208 g, 96 %) is admixed
without further purification with a suspension of 3.9 g
(0.1 mole) of sodium amide and 70 ~1 of anhydrous
benzene ~! whereupon,after the termination of the evolution
of ammonia gas,at room temperature 19 g (0.1 mole) of
~-toluene-sulfonyl chloride are added. ~he addition
- having been completed the reaction mixture is stirred
at room temperature for some hours and washed successive-
ly with 40 ml of water, 40 ml of a saturated sodium
bicarbonate solution and 40 ml of water, and dried over
anhydrous magnesium sulfate. r~o the benzene solution
17.2 g tO.105 mole) of 1-(2-pyrimidinyl)-piperazine
are added and the reaction mixture is heated to boiling
for some hours. ~he reaction mixture is washed with
an aqueous sodium bicarbonate solution and water, the
benzene solution is evaporated in vacuo. ~he residue
is taken up in petrolether and the crystals are filtered.
Ihus 23.65 g of the desired compound are obtained in
the form of white crystals, yield 62 %, m.p.: 78-79 C.
Analysis for the Formula ~21H27N502 (381.49)
calc.: C % = 66.12; H % = 7.13; N % = 18.36;
found: ~ % = 65.85; H % = 7.02; N % = 18.10.
, _ . _ . _, . ., _ _ ,, . . .. _, _ .. _, _ . _, . .
~- ,................ .

- 22 - 13~41
Pre_aration of the compound of the Formula II~
Example 4
8-~4-/4-(2-P rimidin!yl)-l-piperazinyl7-
-butenè-2-~I}-8-àza-spiro/ 4.57decane-7,9-
-dione
Into a hydrogenating apparatus 38.15 g
(0.1 mole) of 8-~4-r 4-t2-Pyrimidinyl)-l-piperazinyl7-
-but-2-in-yl}-8-aza~spirol 4.57decane-7,9-dione, 150 ml
of ethanol, 1 g of a palladium/charcoal catalyst and
o 1 ml of "Quinoline S" deactivator are weighed inO ~he
reaction mixture is hydrogenated at room temperature
until the theoretical hydrogen amount (1 molar
equivalent) is taken up. ~he catalyst is filtered and
the filtrate is evaporated. ~hus 37.2 g of the desired
compound are obtained, yield ~7 ~.
Analysis for the Formula C21H2gNsO2 (383-5)
calc.: ~ % = 65.77, H % = 7.62; N % = 18.26;
found: ~ % = 65.18, H ~o = 7.47; N % = 18.15.
Preparation of the com~ound of the Formula III
xample 5
8-~za-spiroL4.~7decane-7,9-dione-8-~rop-2-
... . . . . . . . . . . .
-ine
Into a round-bottomed flask equip~ed with
a stirrer, dropping funnel and reflux condenser a
mixture of 167~2 g (1.0 mole) of 8-aza-spiro~ 4.~ -
decane-7,9-dione, 130.86 g (1.1 moles) of propargyl
bromide, 138.2 g (1.0 mole) of potassium carbonate

1 ~O~Ai
-- 23 --
and 250 ~,nl of acetonitrile are ad-edO The reaction
mixture is ~leated to boiling under stirring for some
hours, then cooled to room température, filtered and
the solvent is removed. Thus 178.6 g of the desired
compound are obtained, yield 87 %, b.p.: 150 C/53.31 Pa,
Colourless viscous oil.
Analysis for the ~ormula C12H15N02 (205.26)
calc.: C % = 70.22; H % = 7.36; N % = 6.82;
found: C % = 71.10; H % = 7.42; N % = 6.80.
Example 6
One proceeds accor~in~ tO Example 1 except
that potassium carbonate is replaced by 105.9 g
(1.0 mole) of sodium carbonate. ~hus 162.2 g of the
p~oduct defined in Example 5 are obtained, yield 79 %,
b.p.: 150 C/53~31 Pa~
Example 7
One proceeds according to Example 5 except
that acetoni-trile i5 replaced by 250 ml of tetrahydro-
furane. Thus 149.84 g of the product according to
Example 5 ~re obtained, yield 73 %, b.p.: 150 C/53.31 Pa.
Exam~le 8
One proceeds according to Example 5 except
that acetonitrile is replaced ~y 240 ml of dioxaneO
Thus 170.4 g of the product according to Example 5
are obtained, yield 83 %, bop~: 150 C/53032 Pa.

1300141
~4
Example 9
One proceeds according to Example 5 except
bhat acetonitrile is replaced by 320 ml of ethyl
acetabe. ~hus 145.7 ~- of the product according to
Example 5 a~e obtained, yield 71 %, b.p.: 150 C/53~32 Pa,
Example 10
One proceeds according to Example 5 except
that acetonitrile is replaced by 290 ml of acetone.
~hus 153.95 g of the product according to Example 5
are o~tained,l yield 75 %, b.p.: 150 C/53.32 Pa.
Example ll
One procèeds according to Example 5 except
that acetonitrile is replaced by 250 ml of methyl
ethyl ketone. ~hus 178.6g ~ the product according to
Example 5 are obtained,l yield 87 %,` b.p.: 150 C/53.32 Pa.
. _