U.S. patent application number 12/683713 was filed with the patent office on 2010-05-06 for process for preparation of irbesartan.
This patent application is currently assigned to ALEMBIC LIMITED. Invention is credited to Pandurang Balwant Deshpande, Parven Kumar Luthra, Pinky Tarak Parikh, Hitesh Kantilal Patel, Dhiraj Mohansinh Rathod.
Application Number | 20100113798 12/683713 |
Document ID | / |
Family ID | 37635900 |
Filed Date | 2010-05-06 |
United States Patent
Application |
20100113798 |
Kind Code |
A1 |
Deshpande; Pandurang Balwant ;
et al. |
May 6, 2010 |
PROCESS FOR PREPARATION OF IRBESARTAN
Abstract
A process for the preparation of Irbesartan of formula (I) using
the step of, ##STR00001## reacting biphenyl derivative of formula
(VIa) ##STR00002## wherein R represents a group selected from
--CONH.sub.2 or compound of formula ##STR00003## wherein X
represents H or C.sub.1-4 alkyl, preferably methyl; or any other
such group which can be converted to cyano group, with 1-veleramido
cyclopentane carboxylic acid of formula (V) ##STR00004## in the
presence of an acid in an organic solvent to give biphenyl
derivative of formula (VIIa) ##STR00005## wherein R has the same
meaning as mentioned hereinabove.
Inventors: |
Deshpande; Pandurang Balwant;
(Vadodara, IN) ; Luthra; Parven Kumar; (Vadodara,
IN) ; Rathod; Dhiraj Mohansinh; (Vadodara, IN)
; Patel; Hitesh Kantilal; (Vadodara, IN) ; Parikh;
Pinky Tarak; (Vadodara, IN) |
Correspondence
Address: |
VOLPE AND KOENIG, P.C.
UNITED PLAZA, SUITE 1600, 30 SOUTH 17TH STREET
PHILADELPHIA
PA
19103
US
|
Assignee: |
ALEMBIC LIMITED
Vadodara
IN
|
Family ID: |
37635900 |
Appl. No.: |
12/683713 |
Filed: |
January 7, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11406919 |
Apr 19, 2006 |
7652147 |
|
|
12683713 |
|
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|
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Current U.S.
Class: |
548/253 |
Current CPC
Class: |
C07D 403/10 20130101;
C07C 2601/08 20170501; C07C 233/52 20130101; C07C 231/02 20130101;
C07C 231/02 20130101 |
Class at
Publication: |
548/253 |
International
Class: |
C07D 257/04 20060101
C07D257/04 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 28, 2005 |
IN |
1360/MUM/2005 |
Claims
1. A process for the preparation of Irbesartan of formula (I)
comprising step of, ##STR00036## reacting biphenyl derivative of
formula (VIa) ##STR00037## wherein R represents a group selected
from --CONH.sub.2 or compound of formula ##STR00038## wherein X
represents H or C.sub.1-4 alkyl, preferably methyl; or any other
such group which can be converted to cyano group, with 1-veleramido
cyclopentane carboxylic acid of formula (V) ##STR00039## in the
presence of an acid in an organic solvent to give biphenyl
derivative of formula (VIIa) ##STR00040## wherein R has the same
meaning as mentioned hereinabove.
2. The process as claimed in claim 1, wherein said acid is selected
from the group consisting of organic and inorganic acids or mixture
thereof.
3. The process as claimed in claim 2, wherein the organic acid is
selected from the group comprising methane sulfonic acid and
p-toluene sulfonic acid.
4. The process as claimed in claim 2, wherein the inorganic acid is
sulfuric acid.
5. The process as claimed in claim 1, wherein said organic solvent
is selected from the group consisting of C.sub.1-8 aromatic
hydrocarbons or mixture thereof.
6. The process as claimed in claim 5 wherein C.sub.1-8 aromatic
hydrocarbons is toluene.
7. A process for the preparation of Irbesartan of formula (I)
comprising steps of: ##STR00041## (i) reacting biphenyl derivative
of formula (Via) ##STR00042## wherein R represents a group selected
from --CONH.sub.2 or compound of formula ##STR00043## wherein X
represents H or C.sub.1-4 alkyl, preferably methyl; or any other
such group which can be converted to cyano group, with 1-veleramido
cyclopentane carboxylic acid of formula (V), ##STR00044## in the
presence of an acid in an organic solvent to give biphenyl
derivative of formula (VIIa); ##STR00045## wherein R has the same
meaning as mentioned hereinabove; (ii) converting the compound of
formula (VIIa) to compound of formula (VII); ##STR00046## (iii)
converting the compound of formula (VII) obtained in step (ii) to
Irbesartan of formula (I) by reacting the compound of the formula
(VII) with tributyl tin azide in o-xylene to give Irbesartan of
formula (I).
8. The process as claimed in claim 7, wherein said acid is selected
from the group consisting of organic and inorganic acids or mixture
thereof.
9. The process as claimed in claim 8, wherein the organic acid is
selected from the group comprising methane sulfonic acid and
p-toluene sulfonic acid.
10. The process as claimed in claim 8, wherein the inorganic acid
is sulfuric acid.
11. The process as claimed in claim 7, wherein said organic solvent
is selected from the group consisting of C.sub.1-8 aromatic
hydrocarbons or mixture thereof.
12. The process as claimed in claim 11 wherein C.sub.1-8 aromatic
hydrocarbons is toluene.
13. A process for the preparation of Irbesartan of formula (I)
comprising step of, ##STR00047## reacting biphenyl derivative of
formula (Vib) ##STR00048## wherein A represents protected
tetrazolyl group with 1-veleramido cyclopentane carboxylic acid of
formula (V) ##STR00049## in the presence of an acid in an organic
solvent to give biphenyl derivative of formula (VIIb) ##STR00050##
wherein A has the same meaning as mentioned hereinabove.
14. The process as claimed in claim 13, wherein said acid is
selected from the group consisting of organic and inorganic acids
or mixture thereof.
15. The process as claimed in claim 14, wherein the organic acid is
selected from the group comprising methane sulfonic acid and
p-toluene sulfonic acid.
16. The process as claimed in claim 14, wherein the inorganic acid
is sulfuric acid.
17. The process as claimed in claim 13, wherein said organic
solvent is selected from the group consisting of C.sub.1-8 aromatic
hydrocarbons or mixture thereof.
18. The process as claimed in claim 17 wherein C.sub.1-8 aromatic
hydrocarbons is toluene.
19. A process for the preparation of Irbesartan of formula (I)
comprising steps of: ##STR00051## (i) reacting biphenyl derivative
of formula (Vib) ##STR00052## wherein A represents protected
tetrazolyl group with 1-veleramido cyclopentane carboxylic acid of
formula (V) ##STR00053## in the presence of an acid in an organic
solvent to give biphenyl derivative of formula (VIIb). ##STR00054##
wherein A has the same meaning as mentioned hereinabove; (ii)
deprotecting the protected tetrazolyl group present in the compound
of formula (VIIb) to Irbesartan of formula (I) by hydrolysis or
hydrogenolysis.
20. The process as claimed in claim 19, wherein said acid is
selected from the group consisting of organic and inorganic acids
or mixture thereof.
21. The process as claimed in claim 20, wherein the organic acid is
selected from the group comprising methane sulfonic acid and
p-toluene sulfonic acid.
22. The process as claimed in claim 20, wherein the inorganic acid
is sulfuric acid.
23. The process as claimed in claim 19, wherein said organic
solvent is selected from the group consisting of C.sub.1-8 aromatic
hydrocarbons or mixture thereof.
24. The process as claimed in claim 23 wherein C.sub.1-8 aromatic
hydrocarbons is toluene.
25. A process for the preparation of 1-veleramidocyclopentane
carboxylic acid of formula (V) comprising, ##STR00055## reacting
Aminocyclopentane carboxylic acid hydrochloride salt of formula
(IV) ##STR00056## with valeroyl chloride in the presence of a base
and a phase transfer catalyst (PTC) in a suitable solvent and water
to give 1-veleramido cyclopentane carboxylic acid of formula
(V).
26. The process as claimed in claim 25, wherein the phase transfer
catalyst is selected from the group comprising quarternery ammonium
compound, phosphonium compound and cyclic polyethers.
27. The process as claimed in claim 26, wherein the phase transfer
catalyst is selected from the group tetrabutyl ammonium bromide
(TBAB), tetrabutyl ammonium hydrogensulfate, benzalkonium chloride,
cetyl trimethyl ammonium chloride or mixture thereof.
28. The process as claimed in claim 25, wherein the suitable
solvent is selected from the group comprising non polar water
immiscible solvent.
29. The process as claimed in claim 28, wherein the suitable
solvent is selected from toluene, xylene, benzene, dichloromethane,
cyclohexane, hexane, heptane and the mixture thereof.
30. The process as claimed in claim 25, wherein the base is
selected from alkali metal hydroxide, alkaline earth metal
carbonate or bicarbonate.
31. The process as claimed in claim 30, wherein the base is
selected from NaOH or KOH, LiOH, Na.sub.2CO.sub.3, K.sub.2CO.sub.3,
KHCO.sub.3, NaHCO.sub.3, CaCO.sub.3 or mixture thereof.
32. A process of preparation of Irbesartan comprising the steps of:
(i) reacting Aminocyclopentane carboxylic acid hydrochloride salt
of formula (IV) ##STR00057## with valeroyl chloride in the presence
of a base and a phase transfer catalyst (PTC) in a suitable solvent
and water to give 1-veleramido cyclopentane carboxylic acid of
formula (V) ##STR00058## (ii) reacting 4' aminomethyl-2-cyano
biphenyl of formula (VI) with 1-veleramido cyclopentane carboxylic
acid of formula (V) ##STR00059## in the presence of an acid in an
organic solvent to give
1-(2'cyanobiphenyl-4-yl-methylaminocarbonyl)-1-pentanoylamino
cyclopentane of formula (VII). ##STR00060##
33. The process as claimed in claim 32, wherein the phase transfer
catalyst is selected from the group comprising quarternery ammonium
compound, phosphonium compound and cyclic polyethers.
34. The process as claimed in claim 33, wherein the phase transfer
catalyst is selected from the group tetrabutyl ammonium bromide
(TBAB), tetrabutyl ammonium hydrogensulfate, benzalkonium chloride,
cetyl trimethyl ammonium chloride or mixture thereof.
35. The process as claimed in claim 32, wherein the suitable
solvent is selected from the group comprising non polar water
immiscible solvent.
36. The process as claimed in claim 35, wherein the suitable
solvent is selected from toluene, xylene, benzene, dichloromethane,
cyclohexane, hexane, heptane and the mixture thereof.
37. The process as claimed in claim 32, wherein the base is
selected from alkali metal hydroxide, alkaline earth metal
carbonate or bicarbonate.
38. The process as claimed in claim 37, wherein the base is
selected from NaOH or KOH, LiOH, Na.sub.2CO.sub.3, K.sub.2CO.sub.3,
KHCO.sub.3, NaHCO.sub.3, CaCO.sub.3 or mixture thereof.
39. The process as claimed in claim 32, wherein said acid is
selected from the group consisting of organic and inorganic acids
or mixture thereof.
40. The process as claimed in claim 39, wherein the organic acid is
selected from the group comprising methane sulfonic acid and
p-toluene sulfonic acid.
41. The process as claimed in claim 39, wherein the inorganic acid
is sulfuric acid.
42. The process as claimed in claim 32, wherein said organic
solvent is selected from the group consisting of C.sub.1-8 aromatic
hydrocarbons or mixture thereof.
43. The process as claimed in claim 42 wherein C.sub.1-8 aromatic
hydrocarbons is toluene.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. Patent Application
Ser. No. 11/406,919, filed Apr. 19, 2006. This application claims
foreign priority to Indian Application No. 1360/MUM/2005, filed
Oct. 28, 2005.
FIELD OF THE INVENTION
[0002] The present invention relates to an improved process for
preparing Irbesartan of formula (I).
##STR00006##
BACKGROUND OF THE INVENTION
[0003] The chemical name of Irbesartan is
2-Butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-diazasp-
iro[4,4]non-1-en-4-one and formula is C.sub.25H.sub.28N.sub.6O and
molecular weight is 428.53. The current pharmaceutical product
containing this drug is being sold by Sanofi Synthelabo using the
tradename AVAPRO, in the form of tablets.
[0004] Irbesartan is useful in the treatment of diabetic
nefropathy, heart failure therapy and hypertension. Irbesartan is
angiotension II type I (AII.sub.1)-receptor antagonist.
Angiotension II is the principal pressor agent of the
rennin-angiotension system and also stimulates aldosterone
synthesis and secretion by adrenal cortex, cardiac contraction,
renal resorption of sodium, activity of the sympathetic nervous
system and smooth muscle cell growth. Irbesartan blocks the
vasoconstrictor and aldosterone-secreting effects of angiotension
II by selectively binding to the AT.sub.1 angiotension II
receptor.
[0005] U.S. Pat. Nos. 5,270,317 and 5,559,233 describes a process
for the preparation of N-substituted heterocyclic derivatives which
involves reacting a heterocyclic compound of the formula
##STR00007##
[0006] with a (biphenyl-4-yl)methyl derivative of the formula
##STR00008##
[0007] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and t,
z and Hal have the meanings given in said U.S. Pat. No. 5,270,317,
in the presence of an inert solvent such as DMF, DMSO or THF, with
a basic reagent, for example KOH, a metal alcoholate, a metal
hydride, calcium carbonate or triethylamine. The products of the
reaction were purified by chromatography.
[0008] U.S. Pat. Nos. 5,352,788, and 5,559,233, and WO 91/14679
also describe identical alkylation of the nitrogen atom of the
heterocyclic compound with the halo-biphenyl compound using the
same inert solvent and the same basic reagents.
[0009] Also Canadian Patent No. 2050769 describes the alkylation of
the nitrogen atom of the heterocycle of the formula
##STR00009##
[0010] with a compound of the formula
##STR00010##
[0011] wherein X, R.sub.1, Z.sub.1 and Z.sub.6 have the meanings
given therein, in the presence of N,N-dimethylformamide and a basic
reagent, such as alkali metal hydrides for example sodium or
potassium hydride.
[0012] All of the above identified patents describe alkylation in
solvents, such as N,N-dimethylformamide or DMSO, etc. in the
presence of a basic reagent, for example, a metal hydride or a
metal alcoholate etc. The strong bases, such as metal hydride or a
metal alcoholate require anhydrous reaction conditions. Since
N,N-dimethylformamide is used as a solvent, its removal requires
high temperature concentration by distillation, which can result in
degradation of the final product. The product intermediate is also
purified by chromatography which is commercially not feasible and
cumbersome on large scale.
[0013] Another process given in Canadian Patent No. 2050769
provides synthetic scheme as herein given below.
##STR00011##
[0014] This process comprises the steps of protecting carboxylic
group present on cyclopentane ring which is deprotected in
consecutive step by vigourous hydrogenation condition in autoclave
which is operationally difficult at a large scale.
[0015] US Patent No. 2004242894 also discloses the process of
preparation of Irbesartan from 4-bromomethyl biphenyl
2'-(1H-tetrazol(2-triphenylmethyl)5-yl) and Ethyl ester of
1-Valeramido cyclopentanecarboxylic acid in toluene in presence of
base and PTC, and then hydrolyzing the protecting group. However
this requires chromatographic purification.
[0016] This patent also discloses the process of preparation of
tetrazolyl protected Irbesartan using 2,6 lutidine and
oxalylchloride in toluene. However in this process the yield is as
low as 30%.
[0017] US Patent No. 2004192713 discloses the process of
preparation of Irbesartan by condensing the two intermediates via
Suzuki coupling reaction. The reaction scheme is as given herein
below.
##STR00012##
[0018] However, this process has several disadvantages such as use
of the reagents like butyl lithium and triisobutyl borate at low
temp such as -20 to -30.degree. C. under Argon atmosphere condition
which is difficult to maintain at commercial scale.
[0019] WO2005113518 discloses the process of preparation of
Irbesartan by condensing n-pentanoyl cycloleucine (V) with
2-(4-aminomethyl phenyl)benzonitrile (VI) using dicyclocarbodiimide
(DCC) and 1-hydroxy benzotriazole as catalyst to give an open chain
intermediate of formula (VIII) which is then cyclized in the
presence of an acid, preferably trifluoro acetic acid to give cyano
derivative of formula (VII) and which in turn is converted to
Irbesartan by treating it with tributyl tin chloride and sodium
azide.
##STR00013##
[0020] In this application further describes another process
comprising the steps of reacting
2-butyl-1,3-diazaspiro[4,4]non-1-en-4-one monohydrochloride (A)
with 4-bromobenzyl bromide (B) in presence of base and solvent to
give 3-[4-bromobenzyl]-2-butyl-1,3-diazaspiro[4,4]non-1-en-4-one
(C) which is condensed with
2-[2'-(triphenylmethyl-2'H-tetrazol-5'-yl)phenyl boronic acid in
the presence of tetrakis triphenyl phosphine palladium and base to
give Irbesartan (I). However these processes suffer with several
disadvantages such as it uses trifluoroacetic acid for the
cyclization step which is highly corrosive material. The process
requires an additional step of activation by DCC. This step not
only increases number of steps but also create problem in handling
DCC at an industrial scale as it is highly prone to hazard which
makes the process least preferred on a large scale production of
Irbesartan. Further it uses phenyl boronic acid derivative and
triphenyl phosphine complex which are harmful for the skin and eye
tissue and also harmful for respiratory system. Tetrakis triphenyl
phosphine palladium is also a costly material which increases
overall cost for the production of Irbesartan. Moreover the yield
is as low as 22%.
[0021] All the above patents/applications are incorporated herein
as reference.
[0022] In summary, prior art relating to the process for the
preparation of Irbesartan suffers with several drawbacks such as
[0023] i) It requires chromatographic purification of intermediates
at various stages. [0024] ii) It requires specific autoclave
conditions for a deprotection of protecting group. [0025] iii) It
requires maintaining low temperature conditions such as -30.degree.
C. and requires special handling care and air and moisture tight
condition with the reagents such as butyl lithium and triisobutyl
borate. [0026] iv) It uses hazardous and highly corrosive reagents.
[0027] v) It suffers low yield problem. [0028] vi) All the process
is having more number of reaction steps.
[0029] It is therefore, a need to develop a process which not only
overcomes the disadvantages of the prior art but also economical,
operationally simple and industrially applicable. Present inventors
have directed their research work towards developing a process for
the preparation of Irbesartan which is devoid of the above
disadvantages.
OBJECTS OF THE INVENTION
[0030] It is therefore an object of the present invention is to
provide an improved process for the preparation of Irbesartan.
[0031] Another object of the present invention is to provide an
improved process for the preparation of intermediate 1-valeramido
cyclopentanecarboxylic acid which is used in the process of
preparation of Irbesartan.
[0032] Another object of the present invention is to provide a
process which is simple and easy to handle at an industrial
scale.
[0033] A further object of the present invention is to provide a
process which eliminates the use of chromatographic purification at
intermediate stages and provides such kind of purification which is
feasible at commercial scale.
[0034] Yet another object of the present invention is to provide a
process which involves less number of steps to produce Irbesartan
(I).
[0035] Yet another object of the present invention is to provide a
process for the preparation of Irbesartan comprising step of
reacting 4' aminomethyl-2-cyano biphenyl of formula (VI) with
1-veleramido cyclopentane carboxylic acid (V) in an organic solvent
and in the presence of acid.
##STR00014##
[0036] Yet another object of the present invention is to provide a
process for the preparation of Irbesartan without activation the
--COOH group of compound of formula (V).
[0037] Yet another object of the present invention is to provide a
process for the preparation of Irbesartan which does not involve
isolation step of open chain compound of formula VIII and also
without activating --COOH group of compound of formula (V).
##STR00015##
SUMMARY OF THE INVENTION
[0038] Accordingly, present invention provides an improved process
of preparation of Irbesartan comprising steps of: [0039] (i)
reacting 4' aminomethyl-2-cyano biphenyl of formula (VI) with
1-veleramido cyclopentane carboxylic acid (V) in an organic solvent
and in the presence of acid to obtain the compound of the formula
(VII).
[0039] ##STR00016## [0040] (ii) reacting the compound of the
formula (VII) with tributyl tin azide in an organic solvent at
elevated temperature to provide Irbesartan of formula (I).
##STR00017##
[0040] DETAILED DESCRIPTION OF THE INVENTION
[0041] The present invention provides an improved process of
preparation of Irbesartan comprising steps of: [0042] (i) reacting
4' aminomethyl-2-cyano biphenyl of formula (VI) with 1-veleramido
cyclopentane carboxylic acid (V) in an organic solvent and in the
presence of acid to obtain the compound of the formula (VII).
[0042] ##STR00018## [0043] (ii) reacting the compound of the
formula (VII) with tributyl tin azide in an organic solvent at
elevated temperature to provide Irbesartan of formula (I).
##STR00019##
[0044] The reaction in step (i) is carried out at a temperature
equal to the boiling point of the solution. In general it is in the
range of from about 100.degree. C. to about 150.degree. C. The
water which is liberated during the course of the reaction is
removed from the reaction mixture by methods such as azeotropic
distillation or using an apparatus such as dean stark or by any
conventional methods known in the art.
[0045] The solvent mentioned hereinabove is such that it should be
capable of removing the water azeotropically.
[0046] The example of "organic solvent" as mentioned hereinabove
includes but not limited to C.sub.1-8 hydrocarbons such as toluene,
xylene and the like or the mixture thereof.
[0047] The example of the "acid" as mentioned hereinabove includes
but not limited to methane sulfonic acid, p-toluene sulfonic acid,
sulfuric acid and the like or the mixture thereof.
[0048] After the completion of reaction the solvent is removed from
the reaction mass by distillation either under vacuum or
atmospheric pressure. The residue is dissolved in solvent such as
Ethyl acetate, dichloromethane, chloroform and the like which is
then washed with base solution. Base is selected from the group
comprising NaOH, KOH, LiOH, NaHCO.sub.3, KHCO.sub.3,
Na.sub.2CO.sub.3, K.sub.2CO.sub.3 and the like or mixture thereof.
Organic phase is separated and distilled out completely under
vacuum. The residue is leached with non-polar solvent which
includes but not limited to Methyl t-butyl ether, diisopropyl
ether, diethylether, cyclohexane and the like or mixture thereof.
The product is isolated by filtration or decandation or centrifugal
methods.
[0049] The solid is dried under vacuum at 50-60.degree. C. to give
compound of formula (VII).
[0050] The conversion of cyano group to tetrazolyl group of
Irbesartan is done as per the methods known in the art.
[0051] In the reaction in step (ii), compound (VII) obtained in
step (i) is reacted with tributyl tin azide in organic solvent such
as o-xylene at reflux temperature for 80 hours to give the crude
Irbesartan.
[0052] The mass is treated with 1N NaOH. The phases were separated
and aq. phase is washed with o-xylene and isopropyl ether. Aqueous
phase is treated with charcoal, filtered through hyflobed and then
treated with 3N HCl. The product title compound is filtered, washed
with water and dried under vacuum at 60.degree. C. The product is
crystallized from 95% ethanol to give Irbesartan of formula
(I).
[0053] Starting material 1-veleramidocyclopentane carboxylic acid
of formula (V) is prepared by reacting Aminocyclopentane carboxylic
acid hydrochloride salt of formula (IV) with valeroyl chloride in
the presence of pyridine.
##STR00020##
[0054] In another embodiment of the present invention, the starting
material 1-veleramido cyclopentane carboxylic acid of formula (V)
is prepared by an improved process which comprises reacting
Aminocyclopentane carboxylic acid hydrochloride salt of formula
(IV)
##STR00021##
[0055] with valeroyl chloride in the presence of a base and a phase
transfer catalyst (PTC) in a suitable solvent to give 1-veleramido
cyclopentane carboxylic acid of formula (V).
##STR00022##
[0056] The example of the PTC as mentioned hereinabove includes but
not limited to quarternery ammonium compound, phosphonium compound
and cyclic polyethers such as tetrabutyl ammonium bromide (TBAB),
tetrabutyl ammonium hydrogensulfate, benzalkonium chloride, cetyl
trimethyl ammonium chloride, and the like or the mixture
thereof.
[0057] The suitable solvent as mentioned hereinabove is selected
from the group of non polar water immisible solvent.
[0058] The example of the non polar water immisible solvent
mentioned hereinabove includes but not limited to toluene, xylene,
benzene, dichloromethane, cyclohexane, hexane, heptane and the like
or the mixture thereof.
[0059] The example of the base as mentioned hereinabove is selected
from the group comprising alkali metal hydroxide, alkaline earth
metal carbonate or bicarbonate such as NaOH or KOH, LiOH,
Na.sub.2CO.sub.3, K.sub.2CO.sub.3, KHCO.sub.3, NaHCO.sub.3,
CaCO.sub.3 and the like or mixture thereof.
[0060] In another embodiment, the process of preparation of
Irbesartan comprises the steps of: [0061] (i) reacting
Cyclopentanone of formula (II) with sodium cyanide in the presence
of ammonium chloride and aqueous ammonia in methanol to give the
1-Aminocyclopentane carbonitrile of formula (III).
[0061] ##STR00023## [0062] (ii) reacting 1-Aminocyclopentane
carbonitrile of formula (III) obtained in above step (i) with
aqueous HCl to give 1-Amino cyclopentane carboxylic acid as
hydrochloride salt of formula (IV)
[0062] ##STR00024## [0063] (iii) reacting Aminocyclopentane
carboxylic acid hydrochloride salt of formula (IV) obtained in
above step (ii) with valeroyl chloride in the presence of base and
phase transfer catalyst in a suitable solvent and water to give
1-veleramido cyclopentane carboxylic acid of formula (V);
[0063] ##STR00025## [0064] wherein the said PTC is tetrabutyl
ammonium bromide, the said solvent is toluene and the said base is
NaOH. [0065] (iv) reacting 1-veleramidocyclopentanecarboxylic acid
compound of formula (V) obtained in above step (iii) with 4'
aminomethyl-2-cyano biphenyl of formula (VI) in a solvent such as
toluene and in the presence of methane sulfonic acid to give
compound of formula (VII).
[0065] ##STR00026## [0066] (v) reacting
2-(n-Butyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-4-oxo-1,3
diazaspiro[4.4]non-1-ene-4-one of formula (VII) obtained in above
step (iv) with tributyl tin azide in o-xylene to give the title
compound Irbesartan of formula (I).
##STR00027##
[0067] In another embodiment of the present invention, an improved
process for the preparation of Irbesartan comprises steps of:
[0068] (i) reacting biphenyl derivative of formula (VIa) with
1-veleramido cyclopentane carboxylic acid (V) in an organic solvent
and in the presence of an acid to obtain the compound of the
formula (VIIa).
##STR00028##
[0069] wherein R represents the group selected from --CONH.sub.2 or
compound of formula
##STR00029##
[0070] where X is H or C.sub.1-.sub.4 alkyl; preferably methyl;
[0071] or any other such group which can be converted to cyano
group,
[0072] wherein the said "acid" and "organic solvent" is selected
from the group as defined earlier. [0073] (ii) converting the
compound of formula (VIIa) to compound of formula (VII).
[0073] ##STR00030## [0074] (iii) reacting the compound of the
formula (VII) with tributyl tin azide in an organic solvent at
elevated temperature to provide Irbesartan of formula (I).
##STR00031##
[0075] The conversion of compound of formula (VIIa) to compound of
formula (VII) is performed by conventional methods known in the
art.
[0076] When R represents --CONH.sub.2, the conversion of compound
of formula (VIIa) to compound of formula (VII) is carried out in
the presence of thionyl chloride.
[0077] When R represents compound of formula
##STR00032##
[0078] wherein X has the same meaning given above; the conversion
of compound of formula (VIIa) to compound of formula (VII) is
carried out in polar solvent and in the presence of phosphorous
oxychloride.
[0079] In another embodiment of the present invention, it provides
an improved process for the preparation of Irbesartan comprises
steps of: [0080] (i) reacting biphenyl derivative of formula (VIb)
with 1-veleramido cyclopentane carboxylic acid (V) in an organic
solvent and in the presence of an acid to obtain the compound of
the formula (VIIb).
##STR00033##
[0081] wherein A represents protected tetrazolyl group.
[0082] Suitable protecting groups of protected 1H-tetrazol-5-yl are
the protecting groups customarily used in tetrazole chemistry,
especially triphenylmethyl, unsubstituted or substituted, for
example nitro-substituted, benzyl, such as 4-nitrobenzyl, lower
alkoxymethyl, such as methoxymethyl or ethoxymethyl, lower
alkylthiomethyl, such as methylthiomethyl, and 2-cyanoethyl, also
lower alkoxy-lower alkoxymethyl, such as 2-methoxyethoxymethyl,
benzyloxymethyl and phenacyl.
[0083] wherein the said "acid" and "organic solvent" is selected
from the group as defined earlier. [0084] (ii) deprotecting the
protected tetrazolyl group present in the compound of formula
(VIIb) by known methods to get Irbesartan of formula (I)
[0085] For example triphenylmethyl is customarily removed by means
of hydrolysis especially in the presence of an acid, for example in
the presence of hydrogen halide, advantageously in an inert
solvent, such as haloalkane or an ether, for example in
dichloromethane or dioxane, and with heating; or by hydrogenolysis
in the presence of hydrogenation catalyst, 4-nitrobenzyl is
removed, for example by hydrogenolysis in the presence of
hydrogenation catalyst; methoxymethyl or ethoxymethyl is removed,
for example by treatment with a lower alkyl tin bromide such as
triethyl- or tributyl-tin bromide; methylthiomethyl is removed for
example by treatment with trifluoroacetic acid; 2-cyanoethyl is
removed, for example, by hydrolysis, for example with hydrochloric
acid; and benzyloxymethyl and phenacyl are removed, for example by
hydrogenolysis in the presence of a hydrogenation catalyst.
[0086] In another embodiment of the present invention, an improved
process for the preparation of Irbesartan comprises steps of:
[0087] (i) reacting 4' aminomethyl-2-cyano biphenyl of formula (VI)
with 1-veleramido cyclopentane carboxylic acid of formula (V)
[0087] ##STR00034## [0088] in toluene and in the presence of
methane sulfonic acid, without activating the --COOH group of
compound of formula (V) and without isolating open chain compound
of formula (VIII) to give
1-(2'cyanobiphenyl-4-yl-methylaminocarbonyl)-1-pentanoylamino
cyclopentane of formula (VII).
[0088] ##STR00035## [0089] (ii) converting the compound of formula
(VII) obtained in step (i) to Irbesartan of formula (I) by reacting
the compound of the formula (VII) with tributyl tin azide in
o-xylene to give Irbesartan of formula (I).
[0090] The process of the present invention has following
advantages: [0091] (i) It eliminates the requirement of
chromatographic purification of intermediates at various stages and
provides a process which is economical, operationally simple and
industrially applicable. [0092] (ii) The process provides less
number of steps as it eliminates the steps of protection and
deprotection. [0093] (iii) The process is simple and easy to handle
and does not require special handling care or critical temperature
conditions. [0094] (iv) It eliminates the use of reagents which is
greatly air and moisture sensitive. [0095] (v) It does not require
tedious step of activation of carboxylic group of compound of
formula (V) using dicyclocarbodiimide (DCC) which is not only
difficult in handling but highly prone to hazard.
[0096] The following examples illustrate the invention further and
do not limit the scope of the invention in any manner.
Example-1
Preparation of
2-(n-Butyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-4-oxo-1,3
diazaspiro[4.4]non-1-ene-4-one
[0097] 4'aminomethyl-2-cyano biphenyl (50 g) (VI) is added to
toluene (2 Liter) and methane sulfonic acid (19 ml) and stirred at
ambient temperature.
[0098] 1-Valeramidocyclopentanecarboxylic acid (56.3 g) (V) is
added to the above solution and the mass is refluxed under stirring
for 24 hours and water is separated by dean stark apparatus.
Methane sulphonic acid (4 ml) is added to the reaction mixture and
refluxed under stirring for 24 hours and water is separated by dean
stark apparatus. The reaction mixture is cooled to ambient
temperature and toluene is distilled under vacuum completely. Ethyl
acetate (2 Liter) and 2N sodium hydroxide solution (320 ml) is
added to the residue and stirred for 30 minutes. Two phases are
separated and the organic phase is washed with brine (400 ml). The
organic phase is treated with activated charcoal, filtered through
hyflobed and filtrate is distilled out under vacuum completely.
Methyl t-butyl ether (123 ml) is added to the residue and stirred
for 2 hours at ambient temperature. The product is filtered and
washed with methyl t-butyl ether (90 ml) and suck dried. The
product is dried under vacuum at 50.degree. C. till constant
weight. (Yield: 88%)
[0099] .sup.1H-NMR (CDCl.sub.3): .delta.ppm 0.83 (t,3H);
1.24-136(sex,2H); 1.51-1.61(quent,2H); 1.78-1.98(m,10H); 2.32(t,
2H); 4.71(s, 2H); 7.24-7.73(m,8H)
Example-2
Preparation of
2-(n-Butyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-4-oxo-1,3
diazaspiro[4.4]non-1-ene-4-one
[0100] 4'aminomethyl-2-cyano biphenyl (50 g) (VI) is added to
toluene (2 Liter) and methane sulfonic acid (19 ml) and stirred it
at ambient temperature.
[0101] 1-Valeramidocyclopentanecarboxylic acid (56.3 g) (V) is
added to the above solution and the mass is refluxed under stirring
for 24 hours and water is separated by dean stark apparatus.
Methane sulphonic acid (4 ml) is added to the reaction mixture and
refluxed under stirring for 24 hours and water is separated by dean
stark apparatus. The reaction mixture is cooled to ambient
temperature and 2N sodium hydroxide solution (320 ml) is added to
the residue and stirred for 30 minutes. Two phases are separated
and the organic phase is washed with brine (400 ml). The organic
phase is treated with activated charcoal, filtered through hyflobed
and filtrate is distilled out under vacuum completely. Methyl
t-butyl ether (123 ml) is added to the residue and stirred for 2
hours at ambient temperature. The product is filtered and washed
with methyl t-butyl ether (90 ml) and suck dried. The product is
dried under vacuum at 50.degree. C. till constant weight. (Yield:
90%)
[0102] .sup.1H-NMR (CDCl.sub.3): .delta.ppm 0.83 (t,3H);
1.24-136(sex,2H); 1.51-1.61(quent,2H); 1.78-1.98(m,10H); 2.32(t,
2H); 4.71(s, 2H); 7.24-7.73(m,8H)
Example-3
Preparation of
2-(n-Butyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-4-oxo-1,3
diazaspiro[4.4]non-1-ene-4-one
[0103] 4'aminomethyl-2-cyano biphenyl (50 g) (VI) is added to
xylene (2 Liter) and methane sulfonic acid (19 ml) and stirred it
at ambient temperature.
[0104] 1-Valeramidocyclopentanecarboxylic acid (56.3 g) (V) is
added to the above solution and the mass is refluxed under stirring
for 24 hours and water is separated by dean stark apparatus.
Methane sulphonic acid (4 ml) is added to the reaction mixture and
refluxed under stirring for 24 hours and water is separated by dean
stark apparatus. The reaction mixture is cooled to ambient
temperature and 2N sodium hydroxide solution (320 ml) is added to
the residue and stirred for 30 minutes. Two phases are separated
and the organic phase is washed with brine (400 ml). The organic
phase is treated with activated charcoal, filtered through hyflobed
and filtrate is distilled out under vacuum completely. Diisopropyl
ether (123 ml) is added to the residue and stirred for 2 hours at
ambient temperature. The product is filtered and washed with
diisopropyl ether (90 ml) and suck dried. The product is dried
under vacuum at 50.degree. C. till constant weight. (Yield:
88%)
[0105] .sup.1H-NMR (CDCl.sub.3): .delta.ppm 0.83 (t,3H);
1.24-136(sex,2H); 1.51-1.61(quent,2H); 1.78-1.98(m,10H); 2.32(t,
2H); 4.71(s, 2H); 7.24-7.73(m,8H)
Example-4
Preparation of
2-(n-Butyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-4-oxo-1,3
diazaspiro[4.4]non-1-ene-4-one
[0106] 4'aminomethyl-2-cyano biphenyl (50 g) (VI) is added to
xylene (2 Liter) and p-toluene sulfonic acid (54.8 g) and stirred
it at ambient temperature.
[0107] 1-Valeramidocyclopentanecarboxylic acid (56.3 g) (V) is
added to the above solution and the mass is refluxed under stirring
for 24 hours and water is separated by dean stark apparatus.
P-toluene sulfonic acid (13.7 g) is added to the reaction mixture
and refluxed under stirring for 24 hours and water is separated by
dean stark apparatus. The reaction mixture is cooled to ambient
temperature and 2N potassium hydroxide solution (320 ml) is added
to the residue and stirred for 30 minutes. Two phases are separated
and the organic phase is washed with brine (400 ml). The organic
phase is treated with activated charcoal, filtered through hyflobed
and filtrate is distilled out under vacuum completely. Diisopropyl
ether (123 ml) is added to the residue and stirred for 2 hours at
ambient temperature. The product is filtered and washed with
diisopropyl ether (90 ml) and suck dried. The product is dried
under vacuum at 50.degree. C. till constant weight. (Yield:
84%)
[0108] .sup.1H-NMR (CDCl.sub.3): .delta.ppm 0.83 (t,3H);
1.24-136(sex,2H); 1.51-1.61(quent,2H); 1.78-1.98(m,10H); 2.32(t,
2H); 4.71(s, 2H); 7.24-7.73(m,8H)
Example-5
Preparation of Irbesartan
[0109] Cyclopentanone of formula (II) is reacted with sodium
cyanide in the presence of ammonium chloride and aqueous ammonia in
methanol and water at 60.degree. C. for 1-1.5 hours. The mass is
extracted with dichloromethane whereupon the removal of the solvent
provides 1-Aminocyclopentane carbonitrile.
[0110] 1-Aminocyclopentane carbonitrile of formula (III) obtained
in above step is treated with aq. HCl at 100.degree. C. for 24
hours. The mass is cooled to 0.degree. C. and filtered the solid.
The solid is dissolved in water at 90-95.degree. C. Activated
charcoal is added and stirred. The solution is filtered through
hyflow bed. The pH of the solution is adjusted 5 with TEA. The mass
is cooled to 0-5.degree. C. and stirred for 2 hours whereupon the
product is precipitate out which is filtered to give 1-Amino
cyclopentane carboxylic acid as hydrochloride salt.
[0111] 1-Aminocyclopentane carboxylic acid hydrochloride of formula
(IV) obtained in above step is treated with valeroyl chloride in
the presence of tetrabutyl ammonium bromide and aqueous sodium
hydroxide solution at 0-5.degree. C. for 1 hours. The reaction mix
was diluted with water and toluene and separated the two phases.
The aqueous phase was washed with toluene, chilled and then
acidified to give precipitate. The solid was filtrated and washed
with water to give 1-veleramido cyclopentane carboxylicacid.
[0112] 4'aminomethyl-2-cyano biphenyl (50 g) (VI) is added to
toluene (2 Liter) and p-toluene sulfonic acid (54.8 g) and stirred
it at ambient temperature.
[0113] 1-Valeramidocyclopentanecarboxylic acid (56.3 g) (V)
obtained in above step is added to the above solution and the mass
is refluxed under stirring for 24 hours and water is separated by
dean stark apparatus. P-toluene sulfonic acid (13.7 g) is added to
the reaction mixture and refluxed under stirring for 24 hours and
water is separated by dean stark apparatus. The reaction mixture is
cooled to ambient temperature and 2N sodium hydroxide solution (320
ml) is added to the residue and stirred for 30 minutes. Two phases
are separated and the organic phase is washed with brine (400 ml).
The organic phase is treated with activated charcoal, filtered
through hyflobed and filtrate is distilled out under vacuum
completely. Methyl t-butyl ether (123 ml) is added to the residue
and stirred for 2 hours at ambient temperature. The product is
filtered and washed with methyl t-butyl ether (90 ml) and suck
dried. The product is dried under vacuum at 50.degree. C. till
constant weight. (Yield: 88%)
[0114] 2-(n-Butyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-4-oxo-1,3
diazaspiro[4.4]non-1-ene-4-one of formula (VII) obtained in above
step is reacted with tributyl tin azide in o-xylene at reflux
temperature for 80 hours to give crude Irbesartan. The mass is
treated with 1N NaOH. The phases were separated and aq. phase is
washed with o-xylene and isopropyl ether. Aq phase is treated with
charcoal, filtered through hyflobed and then treated with 3N HCl.
The product title compound is filtered, washed with water and dried
under vacuum at 60.degree. C. The product is crystallized from 95%
ethanol to give Irbesartan. (Yield: 86%).
[0115] .sup.1H-NMR (DMSO d6): .delta.ppm 0.78 (t, 3H); 1.17-1.30
(sex, 2H); 1.40-1.50 (quent, 2H); 1.64-1.66 (m, 2H); 1.80-1.82 (m,
6H); 2.22-2.29 (t, 2H); 4.67 (s, 2H); 7.07 (s, 4H); 7.50-7.68 (m,
4H)
[0116] M.sup.+: 429.6
Example-6
Preparation of Irbesartan
[0117] 4'aminomethyl-2-(1,3-oxazolin-4,4-dimethyl)-1,1' biphenyl
(67.2 g) (VIa, where R is 1,3-oxazolin-4,4-dimethyl-2-yl) is added
to toluene (2 Liter) and methane sulfonic acid (19 ml) and stir it
at ambient temperature.
[0118] 1-Valeramidocyclopentanecarboxylic acid (56.3 g) (V) is
added to the above solution and the mass is refluxed under stirring
for 24 hours and water is separated by dean stark apparatus.
Methane sulphonic acid (4 ml) is added to the reaction mixture and
refluxed under stirring for 24 hours and water is separated by dean
stark apparatus. The reaction mixture is cooled to ambient
temperature and toluene is distilled under vacuum completely. Ethyl
acetate (2 Liter) and saturated sodium bicarbonate solution (320
ml) is added to the residue and stirred for 30 minutes. Two phases
are separated and the organic phase is washed with brine (400 ml).
The organic phase is treated with activated charcoal, filtered
through hyflobed and filtrate is distilled out under vacuum
completely. Methyl t-butyl ether (123 ml) is added to the residue
and stirred for 2 hours at ambient temperature. The product is
filtered and washed with methyl t-butyl ether (90 ml) and suck
dried. The product is dried under vacuum at 50.degree. C. till
constant weight. (Yield: 80%) to give
2-(n-Butyl)-3-[2'(1,3-oxazolin-4,4-dimethyl)-biphenyl-4-ylmethyl]-4--
oxo-1,3 diazaspiro[4.4]non-1-ene-4-one.
[0119]
2-(n-Butyl)-3-[2'(1,3-oxazolin-4,4-dimethyl)-biphenyl-4-ylmethyl]-4-
-oxo-1,3 diazaspiro[4.4]non-1-ene-4-one of formula (VIIa, where R
is 1,3-oxazolin-4,4-dimethyl-2-yl) obtained in above step is
treated with phosphorous oxychloride in a polar solvent to give
2-(n-Butyl)-3-[2'cyanobiphenyl-4-ylmethyl]-4-oxo-1,3
diazaspiro[4.4]non-1-ene-4-one.
[0120] 2-(n-Butyl)-3-[2'cyanobiphenyl-4-ylmethyl]-4-oxo-1,3
diazaspiro[4.4]non-1-ene-4-one of formula (VII) obtained in above
step is reacted with tributyl tin azide in o-xylene at reflux
temperature for 80 hours to give crude Irbesartan. The mass is
treated with 1N NaOH. The phases were separated and aq. phase is
washed with o-xylene and isopropyl ether. Aq phase is treated with
charcoal, filtered through hyflobed and then treated with 3N HCl.
The product title compound is filtered, washed with water and dried
under vacuum at 60.degree. C. The product is crystallized from 95%
ethanol to give Irbesartan. (Yield: 81%)
[0121] .sup.1H-NMR (DMSO d6): .delta.ppm 0.78 (t, 3H); 1.17-1.30
(sex, 2H); 1.40-1.50 (quent, 2H); 1.64-1.66 (m, 2H); 1.80-1.82 (m,
6H); 2.22-2.29 (t, 2H); 4.67 (s, 2H); 7.07 (s, 4H); 7.50-7.68 (m,
4H)
[0122] M.sup.+: 429.6
Example-7
Preparation of Irbesartan
[0123] 4'aminomethyl-2-amide-1,1' biphenyl (54.3 g) (VIa, where R
is --CONH.sub.2) is added to toluene (2 Liter) and methane sulfonic
acid (19 ml) and stir it at ambient temperature.
[0124] 1-Valeramidocyclopentanecarboxylic acid (56.3 g) (V) is
added to the above solution and the mass is refluxed under stirring
for 24 hours and water is separated by dean stark apparatus.
Methane sulphonic acid (4 ml) is added to the reaction mixture and
refluxed under stirring for 24 hours and water is separated by dean
stark apparatus. The reaction mixture is cooled to ambient
temperature and toluene is distilled under vacuum completely. Ethyl
acetate (2 Liter) and 2N sodium hydroxide solution (320 ml) is
added to the residue and stirred for 30 minutes. Two phases are
separated and the organic phase is washed with brine (400 ml). The
organic phase is treated with activated charcoal, filtered through
hyflobed and filtrate is distilled out under vacuum completely.
Methyl t-butyl ether (123 ml) is added to the residue and stirred
for 2 hours at ambient temperature. The product is filtered and
washed with methyl t-butyl ether (90 ml) and suck dried. The
product is dried under vacuum at 50.degree. C. till constant
weight. (Yield: 80%) to give
2-(n-Butyl)-3-[2'amidebiphenyl-4-ylmethyl]-4-oxo-1,3
diazaspiro[4.4]non-1-ene-4-one.
[0125] 2-(n-Butyl)-3-[2'amidebiphenyl-4-ylmethyl]-4-oxo-1,3
diazaspiro[4.4]non-1-ene-4-one of formula (VIIa, where R is
--CONH.sub.2) obtained in above step is treated with thionyl
chloride at reflux for 3.5 hours. The reaction was filtered and the
thionyl chloride removed in vacuo. The residue was dissolved in
toluene and reconcentrated in vacuo. On standing overnight, the
residue crystallized. The crystals were collected and washed with
hexane to give 2-(n-Butyl)-3-[2'cyanobiphenyl-4-ylmethyl]-4-oxo-1,3
diazaspiro[4.4]non-1-ene-4-one.
[0126] 2-(n-Butyl)-3-[2'cyanobiphenyl-4-ylmethyl]-4-oxo-1,3
diazaspiro[4.4]non-1-ene-4-one of formula (VII) obtained in above
step is reacted with tributyl tin azide in o-xylene at reflux
temperature for 80 hours to give crude Irbesartan. The mass is
treated with 1N NaOH. The phases were separated and aq. phase is
washed with o-xylene and isopropyl ether. Aq phase is treated with
charcoal, filtered through hyflobed and then treated with 3N HCl.
The product title compound is filtered, washed with water and dried
under vacuum at 60.degree. C. The product is crystallized from 95%
ethanol to give Irbesartan. (Yield: 85%)
[0127] .sup.1H-NMR (DMSO d6): .delta.ppm 0.78 (t, 3H); 1.17-1.30
(sex, 2H); 1.40-1.50 (quent, 2H); 1.64-1.66 (m, 2H); 1.80-1.82 (m,
6H); 2.22-2.29 (t, 2H); 4.67 (s, 2H); 7.07 (s, 4H); 7.50-7.68 (m,
4H)
[0128] M.sup.+: 429.6
Example-8
Preparation of Irbesartan
[0129] 4'aminomethyl-2-(1-triphenylmethyl-1H-tetrazol-5-yl)-1,1'
biphenyl (118.46 g) (VIb, where A is triphenylmethyl protected
tetrazolyl group) is added to toluene (2 Liter) and methane
sulfonic acid (19 ml) and stir it at ambient temperature.
[0130] 1-Valeramidocyclopentanecarboxylic acid (56.3 g) (V) is
added to the above solution and the mass is refluxed under stirring
for 24 hours and water is separated by dean stark apparatus.
Methane sulphonic acid (4 ml) is added to the reaction mixture and
refluxed under stirring for 24 hours and water is separated by dean
stark apparatus. The reaction mixture is cooled to ambient
temperature and toluene is distilled under vacuum completely. Ethyl
acetate (2 Liter) and saturated sodium bicarbonate solution (320
ml) is added to the residue and stirred for 30 minutes. Two phases
are separated and the organic phase is washed with brine (400 ml).
The organic phase is treated with activated charcoal, filtered
through hyflobed and filtrate is distilled out under vacuum
completely. Methyl t-butyl ether (123 ml) is added to the residue
and stirred for 2 hours at ambient temperature. The product is
filtered and washed with methyl t-butyl ether (90 ml) and suck
dried. The product is dried under vacuum at 50.degree. C. till
constant weight. (Yield: 80%) to give
2-(n-Butyl)-3-[2'(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-ylme-
thyl]-4-oxo-1,3 diazaspiro[4.4]non-1-ene-4-one.
[0131]
2-(n-Butyl)-3-[2'(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-ylm-
ethyl]-4-oxo-1,3 diazaspiro[4.4]non-1-ene-4-one of formula (VIIb,
where A is triphenylmethyl protected tetrazolyl group) obtained in
above step was treated with 5 N HCl in methanol and tetrahydrofuran
at 0-5.degree. C. and then stirred at ambient temperature for
overnight. After completion of reaction tetrahydrofuran and
methanol was distilled out under vacuum. The residue was
partitioned between toluene and 1N sodium hydroxide. Two phases
were separated and aqueous phase was washed with isopropyl ether.
The aqueous phase was adjusted to pH 4.6 by 3N hydrochloric acid.
The product was filtered and washed with water and dried in air to
get Irbesartan. (Yield: 75%)
[0132] .sup.1H-NMR (DMSO d6): .delta.ppm 0.78 (t, 3H); 1.17-1.30
(sex, 2H); 1.40-1.50 (quent, 2H); 1.64-1.66 (m, 2H); 1.80-1.82 (m,
6H); 2.22-2.29 (t, 2H); 4.67 (s, 2H); 7.07 (s, 4H); 7.50-7.68 (m,
4H)
[0133] M.sup.+: 429.6
Example-9
Preparation of 1-Valeramidocyclopentanecarboxylic Acid
[0134] In a 3 necked 250 ml round bottom flask equipped with
mechanical stirrer, was charged with sodium hydroxide solution
(24.1 g dissolved in 100 ml water) and 1-aminocyclopentane
carboxylic acid hydrochloride (25 g) and chilled to 0.degree. C.
under stirring. Tetra butyl ammonium bromide (0.25 g) was added to
the reaction mixture followed by slow addition of a solution of
valeroyl chloride (27.5 g) in toluene (20 ml) during one hour at
0-5.degree. C. under stirring. The reaction mass was stirred for 1
hour at 0-5.degree. C. The reaction mixture was diluted with water
(100 ml) toluene (20 ml) and stirred for 15 minutes. The two phases
were separated. The aqueous phase was washed with toluene (20 ml).
Aqueous phase was chilled to 10.degree. C. and acidified with
hydrochloric acid and stirred it for 1 hour. The product was
filtered and washed with water. The product was dried at 60.degree.
C. till constant weight. (Yield: 22 g; 68%).
[0135] .sup.1H-NMR (DMSOd.sup.6): .delta. ppm 0.819 (t,3H);
1.16-128(sex,2H); 1.37-1.47(quent,2H); 1.59(m,4H);
1.79-1.84(m,2H);1.97-2.05 (m,4H); 8.02(s, 1H); 12.0 (Broad singlet,
1H).
* * * * *