FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
Useful alkylation using Imidazole as a catalyst
APPLICANT:
CALYX CHEMICALS AND PHARMACEUTICALS LTD. 2, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India
Indian Company incorporated under the Companies Act 1956
The following specification particularly describes the invention and the manner in which it is to be performed

TITLE
Useful alkylation using Imidazole as a catalyst
FIELD OF INVENTION
The present invention relates to the effective and advantageous process of alkylation of drug intermediates or their salts using substituted or unsubstituted Imidazole moiety as a catalyst. In particular, the present invention relates to a novel process for effective N-alkylation of key drug intermediates or their salts using substituted or unsubstituted Imidazole moiety (hereinafter called as Imidazole) as a catalyst. The reaction is performed specifically in presence of inexpensive Imidazole, which acts as a catalyst for N-alkylation.
The present invention also relates to O- and S-alkyiation of drug intermediates or their salts in the presence of inexpensive Imidazole, which acts as a catalyst.
BACKGROUND OF INVENTION
Alkylation reaction is a common step in organic synthesis and is well documented in prior art. It is usually carried out by reaction with an alkylating agent possessing a good leaving group in presence of base in an appropriate solvent.
The use of different catalysts for alkylation is well known in the art. The catalysts that are generally used for such reaction are,
Phase transfer catalysts such as quaternary ammonium or phosphonium salts such as tetrabutyl ammonium bromide, tetrabutyl ammonium hydrogen sulphate, benzyl triphenyl phosphonium bromide, ethyl triphenyl phosphonium acetate etc. or low molecular weight polyethylene glycols like PEG-400 or crown ethers.

Many heterogeneous catalysts are also used in the process of alkylation such as Cu/A12O3, Cu/ZnO, and Cu/Cr2O3 etc. Zeolites are also used as catalyst in N-alkylation.
For selective tertiary alkylation of aromatic hydrocarbons, certain homogenous catalysts are used such as combination of AICI3 in presence of CuCl.
For reductive alkylation Copper chromite is used as a catalyst. Alkylaryl secondary amines are prepared by reductive alkylation of primary aromatic amine with aliphatic ketones under hydrogen pressure and using Copper chromite as a catalyst.
Ionic liquids are also used to promote the alkylation of aromatic ring in presence of lewis acid catalyst. Particularly preferred ionic liquids are 1-methyl imidazolium chloride, 1 -ethyl imidazolium chloride, 1-methyl imidazolium hydrogen sulphate, 1-propyl imidazolium tosylate, 2-ethyl pyridinium chloride, 1-ethyl-3-methyl imidazolium methane sulphonate, 1-ethyl-3-methyl imidazolium hydrogen sulphate etc. Several methods for alkylations using ionic liquids are also known in literature.
US5994602 describes a process for the alkylation of aromatics by reacting an aromatic hydrocarbon with an olefin in presence of ionic liquid such as l-alkyl-3-methyl imidazolium halide along with aluminium or gallium dichloride as a Lewis acid.
WO1995021871 also describes the process for the alkylation of paraffin's, isoparrafins or aromatics with olefins in presence of ionic liquid along with the Lewis acid.

WO2007050492 describes the synthesis of alkylated aromatic compounds using ionic liquid as a solvent. The process involves alkylation of aromatic compound with monoolefin in presence of an acid catalyst.
US5824832 provides a process for making linear alkyl benzene using an ionic liquid as a catalyst.
Synthesis 2007, 17, 2653-2659 reports the use of N-methyl imidazole as a promising catalyst for the Aza-Michel addition reaction of N-heterocycles.
All the above references describe the process for alkylation reaction using ionic liquid as a catalyst or as a reaction medium. None of the prior art describes the N-, 0-, and S-alkylation process using ionic liquids or Imidazole as a catalyst. N-methyl imdiazole is a well documented to catalyse the acetylation or acylation reaction of polymers and organic compounds.
The inventors of the present invention surprisingly found out a novel, effective and advantageous process for alkylation, more particularly for N-alkylation of key drug intermediates or their salts by using Imdiazole as a catalyst. The use of Imdiazole is inexpensive and shortens the reaction time, thereby makes the process economic. It improves the yield and purity of final compound. The process is environmentally friendly and contributes to the green chemistry.
OBJECT OF INVENTION
An object of the present invention is to provide an effective and advantageous process of alkylation of drug intermediates or their salts using Imidazole as a catalyst. More particularly, an object of the present invention is to provide a novel, effective and advantageous process for N-alkylation of key drug intermediates or their salts using Imidazole as a catalyst.

A further object of the present invention is to provide a novel process for effective N-alkylation of key drug intermediates or their salts by reacting it with an alkylating agent R1-CH2-Z in the presence of Imidazole as a catalyst.
Another object of the present invention is to provide the use of Imidazole as an effective alkylation catalyst, which promotes the N-alkylation reaction under mild conditions.
Another object of the present invention is to provide the use of Imidazole as an effective alkylation catalyst in monophasic, biphasic or multiphase reaction system.
Another object of the present invention is to provide a novel process for effective N-alkylation of key drug intermediates or their salts with the use of Imidazole as a catalyst in a shorter period of reaction time and thereby making the process cost-effective.
Yet another object of the present invention is to provide a novel process for effective N-alkylation of key drug intermediates or their salts, which leads to another vital drug intermediates.
Yet another object of the present invention is to provide an improved process for the preparation of key drug intermediates or their salts of Sartans and thereby preparation of Sartans and pharmaceutically acceptable salts thereof in good yield and with a high purity.
Yet another object of present invention is to provide effective process for O-alkylation of drug intermediates or their salts by reacting with an alkylating agent R1-CH2-Z using Imidazole as a catalyst and thereby providing an improved process for the preparation of antibacterial drug in good yield and with a high purity.

Yet another object of the present invention is to provide an effective process for O- and S-alkylation of drug intermediates or their salts by reacting with an alkylating agent R1-CH2-Z using Imidazole as a catalyst.
SUMMARY OF INVENTION
According to an aspect of the present invention there is provided an effective and advantageous process for alkylation of key drug intermediates or their salts using Imidazole as a catalyst. More particularly, the present invention provides a novel process for effective N-alkylation of key drug intermediates or their salts by reacting with R1-CH2-Z as an alkylating agent using Imidazole as a catalyst.
The process of the present invention for N-alkylation comprises, reacting drug intermediates of group 'R2-NH-R3' or their salts with an alkylating agent such as R1-CH2-Z in the presence of Imidazole as a catalyst and a base, in an appropriate organic solvent. R1, R2, R3 and Z are as defined, in the detailed description of invention, herein below.
According to another aspect of the present invention there is provided an effective and advantageous process for O- and S-alkylation process of key drug intermediates or their salts by reaction with an alkylating agent R1-CH2-Z in the presence of Imidazole as a catalyst and a base, in an appropriate organic solvent.
DETAILED DESCRIPTION OF INVENTION
The present invention relates to an effective and advantageous process for alkylation of key drug intermediates or their salts using Imidazole as a catalyst. More particularly, the present invention relates to a novel, effective and advantageous process for N-alkylation of key drug intermediates or their salts using Imidazole as a catalyst.

The present invention also relates to an effective and advantageous process for O-and S-alkylation of drug intermediates or their salts using Imidazole as a catalyst.
For the present invention, the term Imidazole or Imidazole moiety is defined as, "unsubstituted or substituted Imidazole", which is represented by following structure,

wherein , R is H, alkyl or substituted alkyl; aryl, or substituted aryl.
In an aspect of the present invention there is provided a novel process for effective N-alkylation of key drug intermediates or their salts, which process comprises, reacting drug intermediates of group R2-NH-R3 or their salts with an alkylating agent such as R1-CH2-Z in the presence of Imidazole as a catalyst and a base, in an appropriate organic solvent.

The process of present invention for N-alkylation using Imidazole as a catalyst is as depicted in Scheme I below,
Scheme I:

wherein,
R is as defined above.
R2 and R3 may be H, alkyl, substituted alkyl, cycloalkyl; aryl, substituted aryl, substituted or unsubstituted 0-, N-, S- containing heterocycles; or R2 or R3 together with NH group forms an unsaturated, saturated or aromatic ring which may be further substituted or interrupted by one or more oxygen and /or nitrogen and/or sulphur atoms or any amino acid or substituted amino acid.
NH group may be a part of a heterocyclic ring or an amine where R2 and R3 are as defined above.
R1 may be H or phenyl, substituted phenyl; biphenyl, substituted biphenyl or as defined above for R2 or R3.
Z may be a halogen or a good leaving group.

R2 and R3 along with NH group forms a key drug intermediates of well known drugs such as Irbesartan, Losartan, Valsartan and Telmisartan represented by following structures,

The inventors of the present invention found out that the use of Imidazole as a catalyst makes reaction time shorter and thereby makes the process cost effective. It also improves the yield and purity of the product. Also it improves overall process stability. Thus, makes the process more feasible and industrially viable.
In an embodiment of present invention Imidazole, an alkylation catalyst used in the process of present invention is selected from imidazole, N-methyl imidazole,

N-ethyl imidazole, N-propyl imidazole etc., preferably imidazole or N-methyl imidazole.
In another embodiment of present invention, the alkylation process is carried out in presence of an inorganic or organic bases, selected from triethyl amine, diisopropyl ethyl amine, pyridine, DMAP, lH-tetrazole, potassium t-butoxide, sodium methoxides, NMP, NaH, N-butyl lithium, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, CS2CO3 etc., preferably organic base such as diisopropyl ethyl amine or triethyl amine or inorganic base such as alkali metal hydroxides such sodium hydroxide or potassium hydroxide.
In another embodiment of present invention, the alkylation process is carried out in presence of an appropriate solvent. The process of present invention may be carried out in monophasic, biphasic or multiphase reaction system.
The solvent used in the process may be selected from polar protic or polar aprotic or hydrocarbons or halogenated hydrocarbons or ethers. The polar protic solvents may be selected from water, acetic acid or from alcohols such as methanol, ethanol, n-propanol, n-butanol etc. The polar aprotic solvent may be selected from DMF, DMSO, acetonitrile, acetone, ethyl acetate etc. The hydrocarbon solvents may be selected from toluene, xylene etc. The halogenated hydrocarbons may selected from dichoromethane, 1,1,1-trichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene etc. ethers are selected from diethyl ether, THF, diisopropyl ether etc. The solvents are used alone or in combination with other solvents., preferably solvent selected from polar protic solvent such as water, methanol or ethanol; polar aprotic solvent such as DMF, DMSO, acetone or ethyl acetate; hydrocarbon solvent such as toluene; halogenated hydrocarbons such as dichloromethane or chlorobenzene, used alone or in combination with other solvents.

In another embodiment of present invention the alkylating agent R1-CH2-Z is selected from the group of compounds of formula II or an alkyl halide wherein, R1 is H or an alkyl, preferably H

wherein, Z may be a halogen atom or any good leaving group. R4 is cyano, tetrazole or substituted tetrazole or carbonyl functional group.
In another embodiment of present invention key drug intermediates for N-alkylation are selected from the group consisting of-
(2-butyl-4-chioro-lH-imidazol-5-yl) methanol (drug intermediate of Losartan)
2-n-butyl-l, 3-diazaspiro [4,4] non-l-ene-4-one and its hydrochloride salt (drug intermediate of Irbesartan)



L-valine benzylester and its tosylate salt (drug intermediate of Valsartan)

2-n-propyI-4-methyl-6-(l -methylbenzimidazol-2-yI) benzimidazole (drug intermediate of Telmisartan)

In yet another embodiment of present invention, N-alkylation process is carried out at temperature ranging from 20 to 100 °C, preferably 20 to 80 °C.

In another aspect of the present invention, compounds of formula A, B, C and D or their salts react with the compounds of formula II to give the precursors of Sartans such as Irbesartan, Losartan, Valsartan and Telmisartan respectively.
In another aspect of the present invention there is provided an improved process for preparation of Sartans of formula III, such as Irbesartan (R5 is a), Losartan (R5 is b), Valsartan (R5 is c) and Telmisartan (R5 is d).

wherein R5 is selected from the group (a), (b), (c) or (d), where line on N atom indicates the point of attachment,



by N-alkylation comprising, reacting formula A, formula B, formula C and formula D or their salts respectively,

with an alkylating agent of formula II


wherein, Z and R4 are as defined above,
in presence of Imidazole as a catalyst and a base in an appropriate solvent.
The alkylated compound is then converted to final compound of formula III by well known methods such as conversion of cyano to tetrazole, deprotection of tetrazole etc. When R4 is cyano, the tetrazole moiety on saltans is formed by reaction of alkylated compound with sodium azide in presence of triethylamine hydrochloride and triethylamine. The process is as described in our Indian pending application 1276/MUM/2008, which is incorporated herein by reference.
In another aspect of the present invention there is provided an improved process for preparation of intermediate of an antibacterial drug such as Clarithromycin of compound of formula IV, by O-alkylation comprising, reacting of formula E with an alkylating agent of formula R1-CH2-Z such as alkyl halide in presence of Imidazole as a catalyst and a base in an appropriate solvent.

The process of the present invention for O-alkylation for drug intermediate such as clarithromycin is as depicted in Scheme II below,
Scheme II:

wherein, R, R1 and Z are as defined above,
In another embodiment of present invention, O-alkylation process is carried out at temperature ranging from 0 to 15 °C, preferably 5 to 10 °C.
Further reaction details such as selection of Imidazole catalyst, alkylating agent base, and solvents are as described herein above in the embodiments.

The details of the invention provided in the following examples are given by the way of illustration only and should not be construed to limit the scope of the present invention.
EXAMPLES
Example 1:
Preparation of 4'-(2-buty!-4-oxo-l,3-diaza-spiro[4.4]non-l-en-3-ylmethyI)-biphenyl-2'Carbonitrile: (Intermediate of Irbesartan)

To the stirred slurry of 2-n-butyl-l, 3-diazaspiro [4,4]non-l-ene-4-one (25.0g, 0.1083 moles) in m-chlorobenzene (125.0 ml, 5.0 vol.) was added aqueous sodium hydroxide solution (dissolved 24.259g, 0.6064 moles of NaOH in 125 ml water) at room temperature over a period of 10-20 minutes. The 4'-bromomethyl-biphenyl-2-carbonitrile (29.485g), followed by N-methyl imidazole (1.25g, 5% wt/wt) was added and the reaction mixture was heated for 55-65 °C and maintained for 3-5 hr.
After completion of reaction, the two layers formed during the reaction were separated. The aqueous layer was extracted with m-chlorobenzene (25.0 ml, 1.0 vol.). The combined organic layer was washed with water (25.0 ml, 1.0 vol.). The separated organic layer was distilled under reduced pressure at 55-65 °C to give 4'-(2-butyl-4-oxo-l,3-diaza-spiro[4.4]non-l-en-3-ylmethyl)-biphenyl-2-carbonitrile (40g).

Example 2:
Preparation of 4,-(2-butyl-4-oxo-l,3-diaza-spiro[4.4]non-l-en-3-yImethyl)-biphenyI-2-carbonitrile: (Intermediate of Irbesartan)
To the stirred slurry of 2-n-butyl-l, 3-diazaspiro [4,4]non-l-ene-4-one (25.0g, 0.1083 moles) in dichloromethane (125.0 ml, 5.0 vol.) was added aqueous sodium hydroxide solution (dissolved 24.259g, 0.6064 moles of NaOH in 125 ml water) at room temperature over a period of 10-20 minutes. The 4'-bromomethyl-biphenyl-2-carbonitrile (29.485g), followed by N-methyl imidazole (l-25g, 5% wt/wt) was added and the reaction mixture was heated for 55-65 °C and maintained for 3-5 hr. After completion of reaction, the two layers formed during the reaction were separated. The aqueous layer was extracted with dichlormethane (25.0 ml, 1.0 vol.). The combined organic layer was washed with water (25.0 ml, 1.0 voI.).The separated organic layer was distilled under reduced pressure at 55-65 °C to give 4'-(2-butyl-4-oxo-l,3-diaza-spiro[4.4]non-l-en-3-yImethyl)-biphenyl-2-carbonitrile (40g).

Example 3:
Preparation of (S)-N-{[2'-(l-trityI tetrazol-5-yI)biphenyI-4-yI] methyl}-[l,2-14C]vaIine benzyl ester: (Intermediate of Valsartan)

To the mixture of L-valine benzyl ester tosylate (20.43g, 0.0538 moles) in N,N-dimethylformamide (120.0 ml, 4.0 vol.) was added diisopropyl ethyl amine portion wise at room temperature. The reaction mixture was stirred for 30 minutes at room temperature. The 5-[4'-(bromomethyl)-[l J '-biphenyl]-2-yl]-I-(triphenylmethyl)-lH-tetrazole (30.0g, 0.0538 moles) followed by N-methyl imidazole (1.5 ml, 5% wt/wt) was added portion wise under stirring at room temperature. The reaction mixture was heated to 45-55 °C and maintained for 2-3 hr. After which time, the reaction mass was cooled to 30 °C. Toluene (150.0 ml, 5.0 vol.) and water (45.0 ml) was added to it and stirred for 30 minutes. The layers were separated. Aqueous layer was extracted with toluene (20.0 ml, 1.0 vol.). Organic layers were combined and dried over anhydrous sodium sulphate. The organic layer was distilled under reduced pressure at 45-55 °C to give (S)-N-{[2'-(1-trityl tetrazol-5-yl)biphenyl-4-yl]methyI}~[l,2-14C]valine benzyl ester (31.6g).

Example 4:
Preparation of 2-n-buryI-4-chIoro-l-[2'-(l-triphenylemethyI-lH-tetrazole-5-yl)-l,l'-biphenyl-4-yl)methyl]-lH-imidazole-5-methanol): (Intermediate of Losartan)

To an aqueous solution of sodium hydroxide (dissolved 1.71g, 0.043 moles of NaOH in 100 ml of water) was added 2-butyl-4-chloro-lH-imidazole-5-carbaldehyde (8.0g, 0.043 moles). The reaction mixture was stirred for 10 minutes. The 5-(4'-bromomethyI biphenyl-2-yl)-2-triethyl-2H-tetrazole (25.2g, 0.045 moles) followed by toluene (100 ml) and imidazole (1.25g, 0.018 moles) was added to the reaction mixture. The reaction mixture was stirred for 24 hrs at room temperature. The layers formed during reaction were separated. The organic layer was washed with 10% aqueous NaOH solution (8.0 ml). Further the organic layer was washed with water (2 X 32.0 ml). To the toluene layer, sodium borohydride (0.66g, 0.017 moles) was added followed by methanol (6.6 ml). The resulting mixture was stirred for 3.0 hr. The organic layer was washed with water (2 X 16 ml). This was heated to 65 °C and gradually cooled to 0 °C and was maintained for 3 hr. after which time, the reaction mixture was filtered to give 2-n-butyl-4-chloro-l-[2'-(l-triphenylemethyl-lH-tetrazole-5-yl)-l,l'-biphenyl-4-yl)methyl]-lH-imidazole-5-methanol) (17.9g).

Example 5:
Preparation of 2-n-butyl-4-chloro-l-[2,-(l-triphenylemethyl-lH-tetrazole-5-yl)-l,l'-biphenyI-4-yl) methyI]-lH-imidazoIe-5-methanol): (Intermediate of
Losartan)

To an aqueous solution of sodium hydroxide (dissolved 1.71g, 0.043 moles of NaOH in 100 ml of water)was added 2-butyl-4-chloro-lH-imidazole-5-carbaldehyde (8,0g, 0.043 moles). The reaction mixture was stirred for 10 minutes. The 5-(4'-bromomethyl biphenyI-2-yl)-2-trityI-2H-tetrazole (25.2g, 0.045 moles) followed by toluene (100 ml) and N-methyl imidazole (1.25g, 0.018 moles) was added to the reaction mixture. The reaction mixture was stirred for 24 hrs at room temperature. The layers formed during reaction were separated. The organic layer was washed with 10% aqueous NaOH solution (8.0 ml). Further the organic layer was washed with water (2 X 32.0 ml). To the toluene layer, sodium borohydride (0.66g, 0.017 moles) was added followed by methanol (6.6 ml). The resulting mixture was stirred for 3.0 hr. The organic layer was washed with water (2 X 16 ml) This was heated to 65 °C and gradually cooled to 0 °C and was maintained for 3 hr. after which time, the reaction mixture was filtered to give 2-n-butyl-4-chloro-l-[2'-(l-triphenylemethyI-lH-tetrazoIe-5-yl)-l,1'-biphenyl-4-yl) methyI]-lH-imidazole-5-methanol) (18.1g)

Example 6:
Preparation of 2-butyl-4-chloro-l-[(2'-cyanobiphenyl-4-yl)methyl]-5-(hydroxymethyl) imidazole: (Intermediate of Losartan)

To an aqueous solution of sodium hydroxide (dissolved 7.0g, 0.175 moles NaOH in 150 ml of water) was added 2-butyl-4-chloro-lH-imidazole-5-carbaldehyde (25.0g, 0.134 moles). This was stirred for 5-10 minutes. The 4'-(bromomethyl)-2-cyano biphenyl (37g, 0.136 moles) was added to the reaction mixture followed by toluene (150 ml) and imidazole (l.0g, 0.015 moles). The reaction mixture was stirred for 10 hr at room temperature. The two layers were separated. The organic layer was washed with 10% NaOH solution (25.0 ml). Further, the organic layer was washed twice with 100 ml of water. To the toluene layer was added sodium borohydride (1.85g, 0.049 moles) and of methanol (40 ml). The reaction mixture was stirred for 3.0 hr at room temperature. The water was added (100 ml) to it. The reaction mixture was cooled to 0 °C and maintained for 2 hr. After which time, the slurry was filtered to give 2-butyl-4-chloro-l-[(2'-cyanobiphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole (41g).

Example 7:
Preparation of 2%4"-0-Bis(trimethylsilyl)-erythromycin A 9-[0-(l-methoxy-l-methylethyl)oxime]: (Intermediate of Clarithromycin)

To a mixture of toluene (78 ml, 7.8 volumes) and DMSO (78 ml, 7.8 volumes) at 20 °C was added Methyl iodide (2.15 g, 0.015 moles), followed by N-methyl imidazole (0.1 ml, 1% w/v). The reaction mixture was stirred for 10 minutes. The compound of formula E (10 g, 0.0104 moles) was then added to the reaction mixture. The reaction mixture was cooled to 8 - 10 °C and potassium hydroxide (0.92 g, 0.016 moles) was added to the reaction mixture. The resulting mixture was stirred for 2 hrs at 8-10°C temperature. After completion of reaction, triethylamine (5 ml) and water (60 ml, 6 volumes) was added. The layers were separated and the aqueous layer was extracted with toluene (2 X 100ml). The organic layers were combined and washed with water (3 X 200 ml). The organic layer was distilled under reduced pressure at 55 - 60 °C to give compound of formula IV (7.4 g)

We claim
1. A novel and effective process for alkylation of key drug intermediates or
their salts using Imidazole catalyst comprising,
reacting key drug intermediates or their salts with an alkylating agent such
asR1-CH2-Z,
wherein, R1 may be H, alkyl, phenyl, substituted phenyl, biphenyl, substituted biphenyl or R2 or R3; wherein R2 and R3 represents hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, substituted or unsubstituted 0-, N-, S- containing heterocycles; or R2 or R3 together with NH group forms an unsaturated, saturated or aromatic ring which may be further substituted or interrupted by one or more oxygen and /or nitrogen and/or sulphur atoms or any amino acid or substituted amino acid; NH group is a part of a heterocyclic ring or an amine ; Z may be a halogen or a good leaving group,
in the presence of Imidazole catalyst and a base, in an appropriate organic
solvent
2. The process as claimed in claim 1, wherein alkylation of key drug
intermediates or their salts is N-alkylation, O-alkylation or S-alkylation,
preferably N-alkylation or O-alkylation
3. The process as claimed in claim 1, wherein the key drug intermediates or
their salts selected for N-alkylation are consisting of group R2-NH-R3

wherein R2 and R3 represents hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, substituted or unsubstituted 0-, N-, S- containing heterocycles; or R2 or R3 together with NH group forms an unsaturated,

saturated or aromatic ring which may be further substituted or interrupted by one or more oxygen and /or nitrogen and/or sulphur atoms or any amino acid or substituted amino acid;
NH group is a part of a heterocyclic ring or an amine where R2 and R3 are as defined above,
preferably key drug intermediates or their salts are selected from the group consisting of- 2-n-butyl-l, 3-diazaspiro [4,4] non-l-ene-4-one (Formula A, Intermediate of Irbesartan) and its hydrochloride salt, (2-butyl-4-chloro-lH-imidazol-5-yI) methanol (Formula B, Intermediate of Losartan), L-valine benzylester (Formula C, Intermediate of Valsartan) and its tosylate salt and 2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl) benzimidazole (Formula D, Intermedaite of Telmisartan)


4. The process as claimed in claim 1, wherein the key drug intermediate for O-alkylation is preferably compound of Formula E (drug intermediate of Clarithromycin)

5. The process as claimed in claim 1, wherein Imidazole catalyst is substituted or unsubstituted Imidazole moiety selected from imidazole, N-methyl imidazole, N-ethyl imidazole or N-propyl imidazole, preferably imidazole or N-methyl imidazole
6. The process as claimed in claim 1, wherein the alkylating agent R1-CH2-Z is selected from the group of compounds of formula II or an alkyl halide wherein, R1 is H or an alkyl


wherein, Z may be a halogen atom or any good leaving group. R4 is cyano, tetrazole or substituted tetrazole or carbonyl functional group, preferably alkylating agent selected for N-alkylation is compound of formula II and alkylating agent selected for O-alkylation is alkyl halide wherein R1 is H
7. The process as claimed in claim I, wherein base is inorganic or organic base, organic base is selected from triethyl amine, diisopropyl ethyl amine, pyridine, DMAP, lH-tetrazole and inorganic base is seleceted from potassium t-butoxide, sodium methoxides, NMP, NaH, N-butyl lithium, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, CS2CO3, preferably organic base such as diisopropyl ethyl amine or triethyl amine or inorganic base such as alkali metal hydroxides such sodium hydroxide or potassium hydroxide is used
8. The process as claimed in claim 1, wherein the alkylation process is carried out in an appropriate organic solvent, alone or in combination, with monophasic, biphasic or multiphase reaction system, preferably solvent used is selected from polar protic, polar aprotic, hydrocarbons, halogenated hydrocarbons or ethers, more preferably, the polar protic solvent is selected from water, acetic acid or from alcohols such as methanol, ethanol, n-propanol, n-butanol, the polar aprotic solvent is selected from DMF, DMSO,

acetonitrile, acetone, ethyl acetate, the hydrocarbon solvents is selected from toluene, xylene, the halogenated hydrocarbons is selected from dichoromethane, 1,1,1-trichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene and ethers is selected from diethyl ether, THF, diisopropyl ether
9. The process as claimed in claim 1 or 2, wherein N-alkylation is carried out
at temperature ranging from 20 to 100 °C, preferably 20 to 80 °C and O-
alkylation is carried out at temperature ranging from 0 to 15 °C, preferably 5
to l0°C
10. The process as claimed in claim 1, 3 or 6, wherein N-alkylation of
compounds of formula A, B, C and D or their salts by reaction with the
compounds of formula II in presence of Imidazole catalyst gives the
precursors of Sartan compounds which are then converted to final Sartan
compounds such as Irbesartan, Losartan, Valsartan and Telmisartan
respectively by well known methods such as conversion of cyano to tetrazole
or deprtotection of tetrazole.