Academic Sciences International Journal of Pharmacy and Pharmaceutical

Sciences
Vol 3, Suppl 5, 2011 ISSN- 0975-1491
Research
Article
AN IMPROVED METHOD OR THE S!NTHESIS O
METO"#OPRAMIDE
A$IM $I!AEI HA#IMEHJANI%
A%
& MO$H'AN ARADI%
(
NAHID ARADI
(
a
aculty of "hemistry% Tar)iat Moallem *ni+ersity% ,- Mofateh St.% Tehran% Iran%
)
De/artment of "hemistry%
Sa+eh )ranch% Islamic A0ad *ni+ersity% Sa+eh% Iran. Email1
0iyaei2tmu.ac.ir
Received: 27 July 2011, Revised and Accepted: 11 Nov 2011
An
(STRA"T
improved method for the synthesis of metoclopramide (MCP) is described by using a suitable solvent for the
condensation step. The advantages of the present wor are (a) using of low amount of the e!cess amine (b) low temperature
and (c) high yield ("#$). Also a new and simple method for the synthesis of MCP.%Cl from MCP is presented.
3ey4ords1 Metoclopramide& Antiemetic& Synthesis& 'astroproinetic& Metoclopramide hydrochloride
Metoclopramide
INTROD*"TION
(MCP) is a very useful
compound with wide applications as a gastrointestinal proinetic
and antiemetic agent()*
.
+ts clinical application is because of
possessing a dopamine , receptor antagonist and wea serotonin
-)%T receptor agonist
*
activities.. ,i/erent routes for the
synthesis of
0
MCP have been described& almost e!clusively in the
patent literatures. 1ne of the problems in the synthesis of MCP is
concern to the condensation step. According to the report by
Clinton et al. condensation of methyl 0)amino)-)chloro)*)
metho!yben2oate with an e!cess of 3&3)diethylethylenediamine
gives low yield of MCP0. Thus& other authors use a 4ewis acid
(SiCl0& 'eCl0 & SnCl0 etc) as catalyst- or activate the
amino group of the amine
(using phosphorous
trichloride) for the
condensation step.#)5
MATERIA#S AND
METHODS
+ndustrial
'eneral
grade of
reagents and solvents were
used without further
puri6cation. ,ouble distilled
water was used in the
reaction. The (
%

and
(.C
3M7 were measured in C,Cl &
,MS1 or , 1 using a 8ruer
Avance).99 M%2
spectrometer. The chemical
shifts are reported in a ppm
relative to TMS. :T)+7 spectra
were
.
recorded using
*
a
Perin);lemr 7<( :ourier
transformation infrared
spectrometer with =8r plates.
COOCH3
OCH3
N
H2N Cl
1
CONHCH2CH2N(C2H
OCH3
Cl
NH
NH2
MCP MCP.HCl
Scheme 51 The
reaction route
for the
/re/aration of
M"P% H"l
Synthesis
+na(liter&
of
*
M"P
neced
round bottom >as e?uipped with
mechanical stirrer& #-.(-5 g (9.-#mol)
3&3)diethylethylenediamine& -9 g
(9.("0 mole) methyl 0)(3)acetyl
amino))-)chloro)*)metho!yben2oate& #
m4 acetic acid& and -5m4 isopropanol
was heated under stirring at #9)#- @C
for 0h. Then& *59m4 water and *5g
3a1% was added and the mi!ture was
stead distilled to remove e!cess
amine. 3e!t the mi!ture was cooled to
room temperature and the precipitate
was 6ltered and washed with water to
give crude MCP (--."g)& m.p. (0A.#& in
a yield of
"#$. Spectroscopic dataB +7 (=8r)
C(cm )
.09(& ..*.&
.**(& ("5.&
(#-.& (#.*&
(-A"& (-.#&
(*".& (*0A&
(9-(&
)
""0&
A*9D (% 3M7
(.99
M%2)& C,Cl ) E (ppm)
A.*0 ((%& br& )3%)& A.(*
((%& s)& #.*" ((%& s)&
0..9 (*%& br)& ..A"
.
(.%&
s)& ..-* (*%& m)& *.-#)
*.#5 (#%& m)& (.9# (#%&
t& F 5.* %2)D (.C 3M7
(5- M%2& C,Cl ) E (ppm)
(#0..& (-5.-& (0#.#&
(.*
J
.A&
((*.#& (((.*& "5.A&
--.A& -(.0& 0#
.
.#& .5.0&
(*.9.
Synthesis
-0.#gofMCP
ofM"P%
was
H"l
dissolved in A*9 m4
methanol&
(..- m4 % 1
and treated
with
activated
charcoal. The
6ltrated was
cooled to
room
temperature
and
hydrochloric
acid was
added (p%
-.-)-.")
*
.
Then (-9 ml
acetone was
added and
the mi!ture
was cooled
to 9 @C. The
precipitate
was 6ltered
and washed
with acetone
to give
Halimehjani et al.
monohydrate of MCP hydrochloride
(#9.(0
)
g)& m.p. (A..*& in a
yield
Int J ha!m ha!m "ci, #ol $, "uppl %,
$7&'$(0
"ON"#*SIO
N
of ".$. Spectroscopic dataB +7 (=8r) C(cm ) .."#& ..9A& .("#&
*"0*&
+n conclusion& we have found that by using isopropanol as
solvent
*#.5& (#.*& (-"5& (-."& (-9(& (.**&
(*#A&
(99(& "(.& A.5& #A9D
(%
J #
) E (ppm) (9.#A ((%& br& ) 3%)& A..0
((%& t& for the condensation step& the reaction condition was improved and
3M7 (.99 M%2& ,MS1 )d
an e!cellent yield of MCP was obtained. Also& by using
methanol
J *
)& ..A. (.%&
s)&
F-.A %2)& 5.#A ((%& s)& #.0" ((%& s)& #.99 (*%& br& 3%
containin
g
aceton
ein the
acidi6catio
n step&
e!cellent yield
of
(.
C 3M7 (5-
M%2&
..#( (*%& m)& ..(( (#%& m)& (.*( (#%& t& F 5.* %2)D
A3NO6#ED'EMENT
,MS1)
d
# ) E (ppm) (#0..& (-5.#& (0A.A& (.(.#& (9".#&
(9A.A& "5..& MCP.%Cl was obtained in simple route that made it more economic.
--.A& 0"."& 05.(&
.0.0& A.-.
Ge than the faculties of Tarbiat Moallem Hniversity for
6nancial
The synthesi2ed MCP and MCP.%Cl pass the tests mentioned in
the
RES*#TS AND
DIS"*SSIONS
support. Ge also than to 8ehdasht =ar and ;mad
,arman Pars
HSP and 8P
pharmacopoeia.
,rug Company for 6nancial support. Many than to A2ad
Hniversity
A
REEREN"ES
5
of Saveh for supporting this
proIect.
Paula et al. have reported an eJcient method for condensation
7 and
of methyl 0 )(3)acetyl amino))-)chloro)*)metho!yben2oate
(. 4arrington
7A&
%amilto
n CG&
8rogde
n
73& 4inewich
KA&
3&3)
diethylethylenediamine
with using acetic acid as
catalyst
and in A#$ isolated yield (Scheme (). So& 6nding a simple
method
7onaniewic2 KA& %eel 7C& LMetodopramideB An
up)dated
with higher yield is interesting for industry. :or this purpose we
revie
w of its
pharmacologic
al properties and
clinica
l
have focused on the condensation method reported by Paula
by
useL. ,rugs ("A.D*- B0-()
0"0.
varyin
g
the
parameters such
as solvent&
amount of materials&
*. Gamorar M& ManIunath SN& Marma MM& L,evelopment
and
5 7 validation of HM spectroscopic method for determination of
reaction time and temperature. Ge have found that by using
metoclopramide hydrochloride in bul and tablet
formulationL.
isopropanol as solvent for the condensation
of and & the
reaction condition was improved and made it possible to
obtain a
+nt K Pharm Pharm Sci& *9((D . B(5()
(50.
high purity product in an e!cellent yield ("#$). Also the
reaction
.. ,umuis A& Sebben M& 8ocaert K& LThe
'astrointestinal
temperature was decrease to #9)#- @C compare to the
previously
Proinetic 8en2amide ,erivatives are Agontist at the
3on)
reported wors ("-)(99 @C) that is very desirable for industrial
Classical -)%T 7eceptor (-)%T.sub.0) Positively
Coupled to
use and energy saving. :urthermore& the amount of e!cess
amine
Adenylat
e Cyclase in 3euronsL. Arch Pharmacol
was decrease that is attracting for industry because of
atom ("A"D.09 B09.)0(9.
economy
.
0. Clinton 71& 4asowsi SC& Salvador HK& 8ates %'&
Carroll PM&
L,erivatives of 0)Amino)*)hydro!yben2oic Acid. +M. AmidesL. K
After improving the condensation process& we have tried to
improve
Am Chem Soc ("-5D 5" B**A-)
**"9.
-. Hmio S& Morimoto A& Heda +& Kapan Patent 9-(A.&
(("5-) OC. A.
the condition for the acidi6cation of MCP to obtain the MCP ("5-D A.B-A0A-sP.
hydrochloride. Hsually& this transformation was carried out in
an
#. Muraami M& +nuai 3& =oda A& 3aano =& LAn
+mproved
anhydrous medium by using of gaseous %Cl. Paula et al. have Synthesis
of
MetoclopramideL. Chem
Phar
m
8ul
l ("5(D
reported a simple procedure for this process by using hydrochloric (" B(#"#)(#"".
acid in water containing acetone in 5# $ yield. Ge have
established
5. =odama T& 3aabayashi M& Aoyama %& %ori T& Kapan
Patent
that hydrochloride of MCP can be obtained in e!cellent yield
(".$)
when MCP base was treated with hydrochloric acid in methanol
and
-#"0*& (("50) OChem. Abstr. ("5-D A*B
(*-(*0tP.
then the precipitation of the products with acetone. ;!cellent
yields A. Paula 7& 8utiewic2 =& TroIanowsa Q& 7us2c2a K& L3ew
.
and elimination of the use of anhydrous solvents and gaseous
%Cl :indings in the Synthesis of
Metoclopramid
eL
are the advantages of this new
process.
Arch.Pharm.(Geinheim) ("A9D .(. B
*"5).99.
.A
9