PROCEDE D'OBTENTION DE PIPERAZIDES D'ACIDES PYRIDINECARBOXYLIQUES

PROCESS FOR THE PREPARATION OF PYRIDINECARBOXYLIC ACID PIPERAZIDES

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
The invention relates to a new process for the
preparation of pyridinecarboxylic acid piperazides having
the general formula I
<IMG> (I)
and their acid addition salts. In the general formula I R1
stands for a methyl or a benzyl group. These compounds are
prepared by reacting an organic or inorganic salt of
pyridinecarboxylic acid with a chloroformic acid ester of
the general formula III
<IMG> (III)
wherein R stands for an alkyl having from 1 to 3 carbon
atoms in the presence of an inert solvent, and the
compound of the general formula IV
<IMG>
(IV)
obtained, wherein R has the same meaning as defined above,
is further reacted with a substituted piperazine of the
general formula V
<IMG> (V)
wherein R1 has the same meaning as defined above,
The compounds of the general formula I possess
valuable cardiovascular and antidepressant properties
and can be obtained by the process according to the
invention almost quantitatively, in an excellent purity.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of pyridinecarboxylic acid pipera-
zides of the general formula I
<IMG> (I)
wherein R1 stands for a methyl or benzyl group, and acid addition salts
thereof, which comprises reacting a salt of an organic or inorganic base and
of pyridinecarboxylic acid of the formula II
<IMG>
(II)
with a chloroformic acid ester of the general formula III
Cl - CO2 - R (III)
wherein R stands for an alkyl having from 1 to 3 carbon atoms, in a homogen-
ous or heterogenous system, in the presence of an inert solvent, and further
reacting the pyridinecarboxylic acid derivative of the general formula IV
obtained
<IMG>
(IV)
wherein R has the same meaning as defined above, with a substituted piperazine
having the general formula V
<IMG> (V)
wherein R1 has the same meaning as defined above, and, if desired, transform-
ing a base of the general formula I obtained into an acid addition salt

thereof in a manner known per se.
2. A process as claimed in claim 1 wherein the obtained pyridinecar-
boxylic acid derivative of general formula IV is not separated from the re-
action mixture in which it is formed prior to reaction with the substituted
piperazine of general formula V.
3. A process as claimed in claim 1 or 2 in which the salt of the
pyridinecarboxylic acid of general formula II is a tertiary amine salt.
4. A process as claimed in claim 1 or 2 in which the salt of the py-
ridinecarboxylic acid of general formula II is a triethylamine or N-methyl-
morpholine salt.
5. A process as claimed in claim 1 or 2 in which the salt of the
pyridinecarboxylic acid of general formula II is an alkali metal salt.
6. A process as claimed in claim 1 or 2 in which the salt of the
pyridinecarboxylic acid of general formula II is the potassium salt.
7. A process as claimed in claim 1 or 2 in which the salt of the
pyridinecarboxylic acid of general formula II is prepared by reaction between
the organic or inorganic base and the pyridinecarboxylic acid and the salt
formed is reacted without separation with the chloroformic acid ester of
general formula III.

Description

-- 2 --
This inv~ntion r~lates ~o a new process for the
preparation of pyridinacarboxylic acid piperazides and
their acid addition sal~s. l-he compounds prepared
according to this invention are encompassed by ~he
general formula I
~ C _ ~ N-R (I~
wherein `
R stands for a methyl or ben7yl group,
and - together with the acid addition salts thereof-
possess valuable cardiovascular and antidepressant
properties.
1~ Compounds of the general formula I are known in
the art and have already been described in "Farmacia"
(Bucuresti) _ , 35, 81 (1962) and in the Hungarian
patent specification No. 162,396.
For the preparation of the compounds having the
general formula I - wherein Rl has the same meaning as
defined above - until now the following three methods
have been used:
a) Pyridinecarboxylic acid is reacted with a
corrssponding piperazine derivative having the general
formula V
Hl~\N-Rl (V)
/ -
- wherein Rl has the same meaning as de~ined above -

~ 5 ~
in a m91t, at a temparature of 140 C ~o 250 C, for
20 to 25 hours~
b) Pyridinecarboxylic acid is converted into a
corresponding ester or ~mide deriva~ive which is then
reacted with a piperazine derivative of the general
formula V - wherein Rl has the samH meaning as defined
above - in the way as described in connection with
method a) above.
c) Pyridinecarboxylic acid i5 transformed into a
corresponding acid chloride which i3 subsequently raacted
with a compound of the general formula V - wherein Rl
has the same ~aning as defined above - at a temperature
of 0 C to 10~ C.
~ethods a) and b) can be accomplished with a yield
of about 40 to 60 ~, while in method c) a yield correspond-
ing to 68 '~ of the theoretical value is achieved. The
product prepared according to any one of the above
methods is purified by distillation in vacuo.
In order to find a reasonable explanation for the
relatively low yield obtained when proceeding according
to method a) the reaction was monitored by thermogravimetry.
It has been found that when melt of pyridine-2-carboxylic
acid is reacted with N-benzylpiperazine or when pyridine-
2-carboxylic acid and N-benzylpiperazine are melted
together, a considerable loss in weight can be observed
already at 120 C, due to a decarboxylating side-reac-
tin. In other words, the main reaction, when carriad
out in an optimum temperature range, i~ accomplished
by a side-reaction which results in a considerable loss
in the end produc~.
~.

3~32
-- 4 --
By method b) above theoretically somewhat more
favourable yields could be expected but, taking into
consideration tha-t for the preparation of ths starting
compounds an additional reaction stsp is needed, the
total yields is the same or even lower than in case of
method a)-
On the other hand, methods b) and c) have
additional disadvan~ages in that in method b) the
preparation of the starting material and the consider~
able amount of ammonia evolving during the reaction
involve pollution problems, and in method c~ the hydro-
chloric acid formad is very difficult to bind end
eliminateO
This inven~ion aims at providing a process for
the preparation of the compounds having the general
formula I, which is devoid of the above drawbacks,
i.e. low or moderate yields, long reaction time, high
temperature, purification with fractionated distilla-
tion in vacuo, and formation of by-products polluting
the environmentO
Now it has surprisingly been found that nearly
all the above disadvantages can be eliminated and an
extremely pure end-product can be obtained by reacting
an organic or mineral salt of pyridinecarboxylic acid
of the formula II
~ COOH (II)
with a chloroformic acid ester having ths general
formula III
~"~

Cl - C02 - R ~IXI)
wherein
R represents an alkyl group having from 1 ~o 3
carbon atoms, in an inert solvent and subsequently
reacting the pyridinecarboxylic acid derivative obtained
of the general Formula IV
~ (IV)
I~ ~ C--O-G02R
wherein
R has the same meanings as above,
preferably without separation, with a piperazine
derivative having the general formula V - wherein Rl
has the same meaning as defined above - and, if desired,
converting a compound of the general formula I obtained
into an acid addition salt thereo~ by reaction with a
suitable organic or inorganic acid.
As an inert solvent any solvent can be used
which does not take part in a chemical reaction under
the given conditions and thus has no effsct on the
progress o~ the reaction. For example tetrahydrofurane,
dimethyl formamide, dimethyl sulfoxide, dioxane and
ethyl acetalte were found to be useful for ~his purposeO
The salt of pyridinecarboxylic acid used as
starting ma'terial can be prepared with a tertiary
amine, e.g. triethyl amine or N-methylmorpholine or
with an inorganic base, such as potassium hydroxide,
but other aLkali metal can also be advantageously
used.
When starting from salts prepared with organic
.

~3~
bases the reaction generally takes place in a homogenous
medium and a previous preparation of salt is not
necessary, while in case of a salt prepared with an
inorganic base the reaction proceeds in a heterogeneous
medium and the salt must be previously preparedO
Reaction can be accomplished in a broad tempera~ure
range without a substantial change in the yield obtained.
The temperature is generally between -20 C and ~40 C~
preferably between -5 C and ~20 G.
When the reaction mixture is treated with water,
the dihydrate of the product precipitates in a crystalline
form and subsequent purifica~ion with fractionated
distillation in vacuo can be omitted.
The main advan~ages of the process according to
the invention over the procssses Icnown in the art are
as follows:
- the reaction terminates within a short time;
- no elevated temperature is required;
- no special equipments are necessary;
- the by-product is not detrimental to the
environmznt;
- the compounds of the general fvrmula I can be
obtained almost quantitatively, in an excellent
purity.
Further details of the invention are illustrated
by the follcIwing non-limiting Examples.
Example 1
Preparation of l-benzyl-4-(2'-picolyl)~piperazine
246.2 9. (200 moles) of pyridlne-2-carboxylic
ao acid are reacted with 202.4 90 (200 moles) of triethyl

~0 3 ~ ~ ~
amine in ethyl acetateO 21701 9, (2 moles) oF ethyl
chloroformate are ~hen added at -5 to 0 C and the
reaction mixture is stirred at this temperature For
30 minutes. Thereafter the mixture is treated wi~h
352.5 9. t2.0 moles) of N-bsnzylpiperazine in 400 ml~
of ethyl acetate for hal~ an hour. When addition of the
above solution is completed the reaction mixture is
stirred for subsequent two hours at 10 C. The ethyl
acetate solution is evaporated in vacuo, then the residue
is dissolved in methynol and precipitated with water.
Yield: 615 9. ~97 ~).
Melting point of the corresponding dihydrate: 81 G to
82 C
Analysis for C17H23N3-2 H20
Calculated: C ~ 64.33 ~; H ~ 7~30 ~; N = 13.24 yO;
Found: C ~ 64025 ~; H - 7.42 ~; N = 13.15 ,~.
Melting point of the corresponding hydrogen fumarate 165 C
to 166 C (literature mOp~ 164 C)- ;
Example 2
Preparation of l-methyl-4-(3'nicotinoyl)-piperazine
16.1 9. (0.1 moles) of potassium salt of nicotinic
acid are reacted with 10.8 9. (Ool moles) of ethyl chloro
formate in a mixture of dimethyl formamide and tetrahydro-
~urane at -5 C to 0 C and 10.0 9. (0.1 moles) of an
ethyl acetate solution of methylpiperazine are added to ~,
the reaction mixture at the same temperature. The
mixture is stirred at ~10 C for two s~bsequent hours
and evaporated in vacuo. Residue is dissolved in di-
chloroethane, the solution obtained is washed with
water, evapora~ed and the residue is fractionated in
.~
-~ :

3sf~
vacuoO
Yield: 18.25 9. (89.0 ~)~
Boiling point: 146 C to 149 C / 0~1 mmHg.
Analysis for CllH15N30:
Calculated: C = 64,36 ~0~ H , 7.3 ~; N _ 20.47 ~;
Found; C , 64~15 ,~; H = 7.43 ~; N = 20~56 ~.
Meltiny point of the corresponding dibhlorohydrate: 130 C~
Example 3
Prepara~ion of l-methyl-4-(4'-isonicotinoyl)-piperazine
12~3 9~ (Ool moles) o~ isonicotinic acid are
transformed into a salt by reaction with 10.1 9, (0.1
moles) o~ N-methylmorpholine in an ethyl acetate solution
at room temperature~ 9.40 9. (0,1 moles) of methyl chloro-
formate are added to the reaction rnixture at a ~emperature
of -6 C to 0 C followed by the addition of 10.0 9~ (0~1
moles) of N-methylpiperazine in ethyl acetate a~ the same
temperature. When addition is completed the reaction
mixture i9 stirred for two hours at ~10 C0 The N-methyl-
morpholine hydrochloride salt obtained is filtered off,
the filtrate is avaporated and residue is fractionated
in vacuo~
Yield: 17.2 9. (84 ~0).
Bo ling point: 147 C to 149 C / 0.2 mmHg.
Analysis for C H N 0:
Calculated: C = 64.36 ~; H = 7~37 ~h; N - 20~47 %~
Found: C ~ 64.52 ~; H ~ 7~48 ~0; N = 20~31 %~
Melting point o~ the corresponding dichlorohydrate: 271 C.