PROCEDE DE PREPARATION DE N-(1-BENZYLPIPERID-4-YL)- BENZAMIDES

PROCESS FOR THE PREPARATION OF N-(1-BENZYLPIPERID-4- YL)-BENZAMIDES

Abrégé anglais

ABSTRACT
Therapeutically useful N-(1-benzylpiperid-4-yl)-
benzamides of the formula:
<IMG>
(wherein X represents a chlorine or bromine atom, R1 represents an
alkyl group containing up to 6 carbon atoms, R2 and R3 represent
hydrogen atoms or one of those symbols represents a chlorine atom
in the 3- or 4-position or a methyl or methoxy group in the 4-position
and the other symbol represents a hydrogen atom, or R2 and R3 together
represent a methylenedioxy group attached to the 3- and 4-positions)
are prepared by a new process which comprises reacting a thiobenzoic
acid derivative of the formula:
<IMG> V
(wherein R4 represents a hydrogen atom, the formyl group, or an
alkanoyl radical containing from 2 to 5 carbon atoms optionally
carrying one to three halogen atoms as substituents) with an alkyl
chlorofonmate containing up to 6 carbon atoms in the alkyl moiety
in an organic solvent and in the presence of triethylamine at a
temperature between -15°C and 0°C, and reacting the resulting
<IMG> VI

(wherein R5 represents an alkyl group containing up to 6 carbon
atoms) in situ with a 1-benzyl-4-aminopiperidine of the formula:
<IMG> IV
at a temperature between 0°C and 20°C, and - when R4 in the
compound so obtained of the formula:
<IMG> VII
is the formyl group or an alkanoyl radical as hereinbefore mentioned
- subjecting the compound to acid hydrolysis to remove the acyl
group and give an N-(1-benzylpiperid-4-yl)-benzamide of general
formula I.

Revendications

C L A I M S
1. A process for the preparation of N-(1-
benzylpiperid-4-yl)-benzamides of the general formula:
<IMG> I
(wherein X represents a chlorine or bromine atom, R1
represents a straight- or branched-chain alkyl group
containing up to 6 carbon atoms, R2 and R3 represent
hydrogen atoms or one of those symbols represents a
chlorine atom in the 3- or 4-position or a methyl or
methoxy group in the 4-position and the other symbol
represents a hydrogen atom, or R2 and R3 together
represent a methylenedioxy group attached to the 3- and
4-positions) which comprises reacting a thiobenzoic acid
derivative of the general formula:-
<IMG> V
(wherein X and Rl are as hereinbefore defined, and R4
represents a hydrogen atom, the formyl group, or an
alkanoyl radical containing from 2 to 5 carbon atoms
optionally carrying one to three halogen atoms as
substituents) with an alkyl chloroformate containing up to
- 13 -

6 carbon atoms in the alkyl moiety in an organic solvent
and in the presence of triethylamine at a temperature
between -15°C and 0°C, and reacting the resulting
thioanhydride of the general formula:
<IMG> VI
(wherein X, R1 and R4 are as hereinbefore defined, and
R5 represents an alkyl group containing up to 6 carbon
atoms) in situ with a 1-benzyl-4-aminopiperidine of the
general formula:-
<IMG> IV
(wherein R2 and R3 are as hereinbefore defined)
at a temperature between 0°C and 20°C, and - when R4 in
the compound so obtained of the general formula:
<IMG> VII
(wherein the various symbols are as hereinbefore defined)
is the formyl group or an alkanoyl radical as hereinbefore
mentioned subjecting the compound to acid hydrolysis to
remove the acyl group and give an N-(1-benzylpiperid-4-
yl)-benzamide of general formula I.
2. A process according to claim 1 in which
- 14 -

the thiobenzoic acid derivative of general formula V is reacted with ethyl
chloroformate.
3. A process according to claim 1 or 2 in which the reactions are
carried out in acetone, methylene chloride or chloroform as the organic sol-
vent.
4. A process according to claim 1 wherein R4 in the reactant of ge-
neral formula V depicted in claim 1 represents the formyl group, or an alkanoyl
radical containing from 2 to 5 carbon atoms optionally carrying 1 to 3 halogen
atoms as substituents, and the resulting product of general formula VII depicted
in claim 1 is hydrolysed by treatment with an aqueous alcoholic solution of
hydrochloric acid at the boiling point of the mixture to give an N-(1-benzyl-
piperid-4-yl)-benzamide of general formula I depicted in claim l.
5. A process according to claim 1 wherein in the general formulae de-
picted in claim 1 X is as defined in claim 1, R1 represents a straight- or
branched-chain alkyl group containing up to 5 carbon atoms, R2 is attached to
the para-position of the benzene ring and represents a hydrogen or chlorine
atom or a methyl or methoxy group, and R3 represents a hydrogen atom.
6. A process according to claim 1 or 5 wherein X represents a chlorine
atom.
7. A process according to claim 1 wherein in the general formulae de-
picted in claim 1 X represents a chlorine atom, R1 represents the methyl group,
R2 is attached to the para-position of the benzene ring and represents a hydro-
gen or chlorine atom or a methyl or methoxy group, and R3 represents a hydrogen
atom.
8. A process according to claim 1 wherein R2 and R3 in general formulae

I, IV and VII depicted in claim 1 represent hydrogen atoms.
9. A process according to claim 1 where m in the general formulae de-
picted in claim 1 X represents a chlorine atom, R1 represents the methyl group
and R2 and R3 represent hydrogen atoms.
10. A process according to claim 1 followed by the step of converting
the N-(1-benzylpiperid-4-yl)-benzamide of general formula I depicted in claim
1 thus obtained into a pharmaceutically acceptable salt.
11. N-(1-benzylpiperid-4-yl)-benzamides of general formulae I depicted
in claim I when prepared by the process claimed in claim 1.
12. The N-(1-benzylpiperid-4-yl)-benzamide of general formula I de-
picted in claim 1 wherein X represents a chlorine atom, R1 represents the
methyl group and R2 and R3 represent hydrogen atoms, when prepared by the pro-
cess claimed in claim 9.
16

Description

9~
THIS I~VENTION relates to a new process for
the preparation of N~ benzylpiperid-4~yl)-benzamides
of the general formula:
X
H2N ~ CONH ~ -CH~
ORl
wherein X represents a chlorine or bromine atom, Rl
repxesents a straight- or branched-chain alkyl group
containing up to six carbon atoms~ for example methyl,
ethyl, propyl, butyl, pentyl or hexyl, R2 and R3 represent
hydrogen atoms or one of those symbols represents a chlorine
atom in the 3- or 4-position or a methyl or methoxy group
in the 4-position and the other symbol represents a hydrogen
atom, or R2 and R3 together represent a methylenedioxy group
attached to the 3- and 4-positions, and pharmaceutically
acceptable salts thereof. The invention is more particularly -
15~ concerned with the preparation of such benzamides wherein X
is as hereinbefore defined, especially a chlorine atom, R
is an alkyl group containing up to~five carbon atoms
(preferably methyl), R2 is a hydrogen atom, or a halogen
atom or a methyl or methoxy group in the 4-position
(preferably hydrogen), and pharmaceutically acceptable salts
thereof.
Benæamide derivatives of general formula I can be
prepared b~ various processes which have been described

~97~
inter alia in, for example, the specification of British
Patent No. 1507463. Of the proce~ses hithert~ described
for their preparation that which involve~ the reaction of
a 2-alkoxy-4-amino-5-halobenzoic acid of the general
formula: `
H2N ~ COOH II
ORl ~ ,
~ .
(wherein X and Rl are as hereinbefore defined), the amino
group of which is optionally protected by an acyl group
~uch as acetyl, rifluoroacetyl, chloroacetyl or
phthaloyl~ with an alkyl chloroformate and the subsequent
reaction of the intermediate mixed anhydride of the general
formula:
I
H2N ~ O ~ C0-0-Co-o-Y III
(wherein X and Rl are as hereinbefore defined and Y
15 represents an alkyl group), or N-acylated derivative ~`
thereof, with an appropriate l-benzyl-4-aminopiperidine
of the general formula~-
2 ~ -CH2 ~ RR3 IV
.~,
.
.

7 ~ 9
(whexein R2 and R3 are as hereinbefore defined) to give ~:
`~ a benzamide derivative of general formula I, or a
corresponding N-acylated compound which can be converted
- by methods known per se into such a derivative, i5 the
5 most facile (cf. Examples 2 and 3 of British Patent No.
1507463). A disadvantage of that process arises from
; the fact that the benzoic acid reactants of general
formula II are relatively insoluble in common, cheap
commercially available solvents, and therefore in such
10 a process an expensive solvent such as anhydrous
tetrahydrofuran is required for the process to be carried
out successfully on a commercial scale and then - even so -
because of the low solubility of the initial benzoic acid
reactant~ yields of the desired benzamide derivatives
of general formula I in excess of 80% of the theoretical
are difficult to attain. ~:
It has now unexpectedly been found after
research and experimentation that benzamide derivatives
of general formula I can be obtained in extremely high
20 yield, viz. about 95% of the theoretical, when a
thiobenzoic acid derivative of the general formula:-
R4_NH~COSH V
~1
~wherein X and Rl are as herelnbefore defined, and R4
- 4 -
... /~
'' : ' ' ~ ' ' '
': :, . " '
... .
:
,, ' ~ .:
: ~

~9~19
represents a hydrogen atom, the formyl group, or an
alkanoyl radical containing from 2 to 5 carbon atoms
optionally carrying one to three halogen atoms, e.g.
chlorine, as substituents) is utiliæed as starting .
material. Moreover, as the thiobenzoic acid derivatives
of general fonmula V are soluble in common commercially ~:~
available solvents, solvents such as acetone, methylene
chloride and chloroform, which are much cheaper than
tetrahydrofuran, can be employed.
According to the present invention, benz~mide
derivatives of general formula I are prepared by the
process which comprises reacting a thiobenzoic acid
derivative of general formula V with an alkyl chloroformate
containing up to 6 carbon atoms in the alkyl moiety ~:
(preferably ethyl chloroformate) in an organic solvent
(preferably acetone) and in the presence of triethylamine
at a temperature between -15C and 0C, and reacting the
resulting thioanhydride of the general formula~
X
O O
R4-NH ~ ~ B-S-CO-R5 VI
OR
(wherein X, Rl and R4 are as hereinbefore defined, and
R5 represents an alkyl group containin~ up to 6 carbon
atoms) in situ with a l-benzyl-4-aminopiperidine of
general formula IV at a temperature between 0C and 20C,
and - when R4 in the compotlnd so obtained of the general
'.,:,
:, . , . ~ ~ . : , ~ , , : , -; ,
:., ~ : : - , ::.: . . . . . : .
. :

~399719
formula:
X
2 ~ ~ R VII
:, ~
(wherein the various symbols are as herei~before defined)
is the formyl group or an alkanoyl radical as hereinbefore
S mentioned - subjecting the compound to acid hydrolysis to
remove the acyl group and give an N~ benzylpiperid-4-
: `
yl)-benzamide of general formula I.
The products of general formula VII, obtainable
in yields of about 95% of the theoretical by the process of
the present invention, may be isolated from the reaction
mixture by removing the organic solvent in:vacuo, dissolving
the residue in chloroform, washing the chloroform solution
with water and an aqueous solution of sodium hydroxide,
drying the solution of the product, e.g. with ~a2SO4, evaporating
lS the chloroform in vacuo and recrystallizing the product of
formula VII from a suitable solvent, for example diethyl
ether, ethanol or methanol.
When R4 in the product of general formula VII
is the formyl group or an alkanoyl radical, the said
group or radical is preferably hydrolysed by heating the
product in an aqueous alcoholic solution oE hydrochloric
acid at the boiling point of the mixture. The resulting ~'
amino compound of general formula I is then isolated by
.
~ - 6

~95~7~ :
diluting the mixture with water, making the solution
alkaline by addition of aqueous sodium hydroxide and
extracting the product with a suitable solvent, for
example methylene chloride or chloroform. The pure
product can then be obtained by evaporating the solvent
and recrystallizing it from a suitable solvent,~ for
example diethyl ether, ethanol or methanol.
The bases of general formula I thus obtained
may be converted by methods known per se into ;~
pharmaceutically acceptable salts, e.g. malates.
fumarates or hydrochlorides,by treatment with an organic
acid such as malic~ or fumaric acid or an inorganic acid
such as hydrochloric acid in ethanol.
The thiobenzoic acids of general formula V
may be prepared from an amide of the general fonmula:
X :
R4-NH ~ O ~ CONH2 VIII ~
: ~ ORl : ~
(wherein X, Rl and R4 are as hereinbefore defined) by
reaction with sodium hydride and carbon disulphide
(I. Shaha]c and Y. Sasson, J. Amer. Chem. Soc. 95, 3440, 1973).
The following Examples illustrate the preparation
of benzamide derivatlves of general formula I by the process
of the present invention.

XAMPLE 1
(a) To a cold stirred solution of 2-methoxy-4-
acetamido-5-chlorothiobenzolc acid (7.79 g; 0~03 moles)
in acetone (80 ml) was added a solution of triethylamine
(4.2 ml, 0.03 moles3 in acetone (10 ml). Whilst
maintaining the temperature between -15 and -10C, a
solution of ethyl chloroformate (2~85 ml; 0.03 moles)
in acetone (10 ml) was slowly added, the reactlon mixture
was stirred at that temperature for one hour, and then
1-benzyl-4-aminopiperidine (5.7 g, 0.03 moles) dissolved
in acetone (10 ml) was added. The temperatur~ of the
reaction mixture was allowed to rise to room temperature
and the mixture was stirred overnight at that temperature.
The solvent was then removed in vacuo, the residue was
treated with water, extracted with chloroform and then
washed successively with aqueous lN sodium hydroxide
solution and water~ The chlorofo~rm solution was dried
(Na2S04), evaporated to dryness and the residue dissolved
in diethyl ether. The soIution was filtered and on
20 cooling, 11.6 g (93% yield) of N~ benzylpiperid-4-yl)-
2-methoxy-4-acetamido-5-chlorobenzamide, m.p. 134-135C,
were obtained.
(b3 A mixture of the above-mentioned product (11 g,
0.026 moles), water (30 ml)~and concentrated hydrochloric
acid (9 ml) was boiled under reflux for 1.5 hours. The
; solution was then cooled, dlluted with water and made
alkaline with a concentrated aqueous solution of sodium
~.
- ~ _
: , :: ;~: .: : - :,

7~-
hydroxide, extracted with chloroform and the chloroform
layer washed with water and dried (Na2SO4). I'he solvent
was evaporated in vacuo to give N~ benzylpiperid-4-yl)
2-methoxy-4-amino-5-chlorobenzamide which was dissolved
in ho~ ethanol and the stoichiometric amount of d,l-
malic acid was added. On cooling, N-(l-benzylpiperid-4-
yl)-2-methoxy-4-amino-5-chlorobenzamide acid malate
(11.26 g; 85.3% yield), m.p. 168-170C (dec.), was
obtained. ;~
EXAMPLE 2
~ ~,
By a similar procedure to that described in
Example 1, ~ benzylpiperid-4-yl)-2-methoxy-4-amino-5-
bromobenzamide was obtained and converted into its
hydrochloride, mOp. 219-221C. Yield in step (a~
: 93.5%.
EXAMPLE 3
By a similar procedure to that described in
Example 1, ~-(1-~-methylbenzylpiperid-4-yl)-2-methoxy-4-
amino-5-chlorobenzamide was obtained and converted into
its hydrochloride, m.p. 234-235C. Yield in step (a)
: g8%.
EX~IPLE 4
By a similar procedure to that described in
Example 1, ~ luorobenzylpiperid-4-yl)-2-methoxy-4-
amino-5-chlorobenzamide was obtained and converted into
its hydrochloride monohydrate, m.p. 256-258C (dec.).
Yield in step (a) : 96%.
g _
.', ..
., ; - . . ..

*~9
EXAMPLE 5
To a cold solution of 2-methoxy-4-amino-5-
chlorothiobenzoic acid ~8.7 g, 0.04 mole) in acetone
~120 ml), triethylamine (5.6 ml, 0.04 moles) was added.
The mixture was stirred and cooled to -15C to -10C
and ethyl chloroformate (3.8 ml; 0.04 moles) was slowly
added. Stirring was continued at that temperature for
1 hour. A solution of l-benzyl-4-aminopiperidine (7.6 g
0.04 moles) in acetone (20 ml) was then slowly added and
the mixture was stirred for 1 hour at -15C to -10C. The
temperature was then allowed to rise to room temperature
and the mixture was stirred at that temperature overnight.
The solvent was then evaporated ln vacuo and the residue
treated with a mixture of chloroform and water. The
chloroform layer was separated, washed with a dilute
solution of sodium hydroxide and then with~water. The
chloroform solution was dried, (Na2S04) and the solvent
evaporated in vacuo to give a solid residue which was
dissolved in hot diethyl ether, filtered and allowed to
crystallize. N-(l-Benzylpiperid-4-yl~-2-methoxy-4-amino-
5-chlorobenzamide (14.1 g, 94.2%), m.p. 193-195C was
thus obtained.
Its hydrochloride monohydrate, m.p. 217-219C,
was prepared by treating the base with aqueous-ethanolic
hydrochloric acid solution.
EXAMPLE 6
~y a similar procedure to that described in
-- 10 --
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.~ " :
~: : : ' .' ` : :
: ~ , , . . : :: ::
,, ~ ~: . ,

7~ ~
Example 5, N-(l-p-methoxybenzylpiperid~4-yl~-2-
methoxy-4-amino-5-chlorobenæamide hydrochloride, m.p.
238~-239C, was prepared. Yield 94.8%.
EXAMPLE 7
By a similar proceduxe to that described in
Example 5, N-tl-p-chlorobenzylpiperid-4-yl)-2-methoxy-4-
amino-5-chlorobenzamide hydrochloride, m.p. 253-256C,
was prepared. Yield 96.3%.
EXAMPLE 8
By a similar procedure to that described in
Example 5, ~ (l-benzylpiperid-4-yl)-2-methoxy-ll-amin
5-chlorobenzamide hydrochloride, m.p. 271-273C, was
prepared. Yield 97.5%.
EXAMPLE 9`
By a similar procedure to that deecribed in
Example 5, N-~l-p-bromobenzylpiperid-4-yl) 2-methoxy-4-
~lino-5-chlorobenzamide hydrochloride, mOp. 242-243C
was prepared. Yield 96~1%.
There can also be prepared by the procedure of
Example 5 the following products of general formula I
using appropriate starting materials of general formula
V and IV:-
N-tl-m-chloro~enzylpiperid-4-yl)-2-methoxy-4-amino-5-
chlorobenzamide hydrochloride, m.p. 249-251C, and
N (l-piperonylpiperid-4-yl)-2-methoxy 4-amino-S-
chlorobenzamide hydrochloride, m.p. 264-266Co
-- 11 --
: -: : :. - ."

~ ~,
The N~ benzyl'piperid-4-yl)-henzamides of
general formula I have pharmacological properties,
principally the ability to antagonize the effects of
dopamine or dopaminergic agents of endogenous or
~xogenous origin. 'rhey may be used for the treatment
of various ailments as mentionedon the first page of
British Patent Specification 1507463 hereinbe~ore
referred to.
.
- 12 -
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