Title of Invention

PROCESS FOR THE PREPARATION OF N-SUBSTITUTED HETERO CYCLIC DERIVATIVES

Abstract

The present invention relates to a process for preparation of N-subsituted 1-[(bipheny1-4-y1) methy1-2-n-buty1-4-spirocyclopentane-2-imidazolin-5-one by suspending 4'-(Bromomethly)[1,1'-bipheny1] drivative in aqueous solution of an in-organic base and adding the solution of 2-buty-1-1,3-diazaspiro[4,4]nonan-4-one in water-miscible organic solvent at temperature of 20(degeeres)C to 55(degeeres)C.Maintaining the reaction mixture at 25(degeeres) C to about reflux temperature of the solvent followed by removing the solvent under reduced pressure,dissolving the residue in water-immiscible organic solvent,distilling under reduced pressure and crystallizing the residue from acetonitrile.

Full Text

Field of the Invention The present invention relates to a process for preparing N- substituted l-[(biphenyl-4-yl) methyl-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one wherein N-substituted groups are cyano or triphenylmethyl tetrazol-5-yl, which are useful as intermediates for the production of Irbesartan. Background of the Invention N-substituted 1 -[(biphenyl-4-yl) methyl-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one has the following structure wherein X is -CN or triphenylmethyl tetrazol-5-yl US Patent No. 5,270,317 discloses the preparation of n-substituted heterocyclic derivatives, which involves reacting a heterocyclic compound of the formula (I) with a (bi-phenyl-4-yl) methyl derivative of the formula (II) wherein R1, R2, R3, R4, R5, t, Z and Hal have the meanings given in the said US Patent 5,270,317, in an inert solvent such as DMF, DMSO or THF, in basic medium, for example in the presence of potassium hydroxide, a metal alcoholate, a metal hydride, calcium carbonate or triethyl amine followed by purification with chromatographic techniques. US Patent No's 5,352,788; 5,559,233 and PCT publication WO 91/14679 also discloses the identical alkylation on the nitrogen atom of the heterocyclic compound with the halogenated biphenyl compound using the same inert solvent and the same basic reagents. European Patent No EP 0,475,898 discloses the alkylation of the nitrogen atom of the heterocyclic compound of the formula (III) with a compound of the formula (IV) wherein X, Ri, Zi, & Z& have the meanings given therein, in the presence of DMF and a basic reagent, such as alkali metal hydrides, for example sodium or potassium hydride. All the above patents discloses alkylation in solvents such as DMF or DMSO, etc., in the presence of a basic reagent, for example, a metal hydride or a metal alcoholate etc which requires anhydrous reaction conditions. Since DMF, DMSO were used as solvents, their removal requires high temperature for distillation, which may results in degradation of the final product. US patent 6,162,922 discloses a process for the preparation of N-substituted heterocyclic derivatives and its salts by reacting a compound of the formula (V) with (bi-phenyl-4-yl) methyl compound of the formula (VI) wherein R and Hal have the meaning given therein. The reaction was carried out using phase-transfer conditions in a water-immiscible organic solvent and an aqueous solution of inorganic bases in presence of a phase transfer catalyst. PCT publication WO 2004/007482 discloses the process for the preparation of 2-butyl-3-[2'-(triphenylmethyl tetrazol-5-yl)biphenyl-4-yl methyl]-!,3-diazaspiro [4,4] non-l-ene-4- one, comprising the step of reacting 2-butyl-l,3-diazaspiro-[4,4]-non-l-ene-4-one with 5-(4'-bromomethylbi-phenyl-2-yl)-l-trityMH-tetrazole in presence of a phase transfer catalyst in a reaction system having first and second phases and an inorganic base, for example KOH, NaOH and LiOH. The process disclosed in US Patent 6,162,922 and the above PCT publication involves the usage of phase transfer catalysts, involves the layer separation, evaporation of solvent till oily residue and finally crystallization involves usage of ether as crystallization solvent. There is a long felt need of the industry for a process for the preparation of N-substituted 1-[(biphenyl-4-yl) methyl-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one, important intermediates in the synthesis of Irbesartan without involving the phase transfer catalysts, chromatographic purifications, but using a water miscible solvent and common inorganic base. Summary of the invention: The main object of the present invention is to provide a process for the preparation of N-substituted 1 -[(biphenyl-4-yl) methyl-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one. Another object of the present invention is to provide the process for the preparation of 4'-[[2-butyl-4-oxo-l ,3-diazaspiro[4,4]non-l -ene-3-yl] methyl][1,1 '-biphenyl]-2-carbonitrile. Another object of the present invention is to provide a process for the preparation of 2-butyl-3-[2'-triphenyl methyltetrazol-5-yl)-biphenyl-4-ylmethyl]-l,3-diazaspiro[4,4]-non-l- ene-4-one. Yet another object of the present invention is to provide a process for N-alkylation without using the phase transfer catalysts. Detailed description of the invention; The preparation of N-substituted l-[(biphenyl-4-yl) methyl-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-ones comprising of the steps ? Adding 4,-(bromomethyl)[l,l'-biphenyl] derivative to aqueous solution of inorganic base ? Adding a solution of 2-butyl-l,3-diazaspiro[4,4]nonan-4-one(dissolved in water-miscible organic solvent) to the above reaction mixture ? Maintaining the reaction mixture at temperature of 25°C to reflux temperature for appropriate time ? Removing the solvent by distillation ? Dissolving the obtained residue in water-immiscible organic solvent ? Washing the reaction mixture with water and sodium hydroxide solution ? Drying the organic layer over desiccant ? Removing the solvent ? Crystallizing the residue from acetonitrile Thus in accordance to the present invention N-Substituted l-[(biphenyl-4-yl) methyl-2-n-butyl-4-spirocyclopentane-2~imidazolin-5-one is prepared by suspending 4'~(Bromo methyl) [l,l'-biphenyl] derivative in aqueous solution of an in-organic base such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, preferably sodium hydroxide and to the above reaction mixture adding the solution of 2-butyl-l,3-diazaspiro[4,4]nonan-4-one dissolved in water-miscible organic solvent such as acetone, acetonitrile, alkanols, 1,4-dioxan or THF, the preferred solvents are acetone and acetonitrile, at temperature of 20°C to 55°C. Maintaining the reaction mixture at 25°C to about reflux temperature of the solvent, preferably 35°C to 65°C for 3 hrs to 12 hrs, more preferably for 4 hrs to 9hrs, followed by removing the solvent under vacuum, dissolving the residue in water-immiscible organic solvent such as chloroform, methylene chloride, ethyl acetate, preferably in ethyl acetate, separating the layers, washing the organic layer with water, sodium hydroxide solution followed by drying the organic layer over desiccant. Distilling under reduced pressure and crystallizing the residue from acetonitrile affords the desired compounds. In case where potassium carbonate or sodium carbonate employed as inorganic base during the reaction, the inorganic salts are removed by filtration before distillation of the water-miscible organic solvent. 2-Butyl-l,3-diazaspiro[4,4]nonan-4-one and 4'-(bromomethyl)[l,r-biphenyl] derivative are prepared by the prior art methods. The invention is further illustrated with a few non-limiting examples Example 1: Preparation of 4,-[[2-butyI-4-oxo-l, 3-diazaspiro [4,4] non-1 -ene-3-yl] methyl-bipheny-2-carbonitrile. 4'-(Bromomethyl)[l,l-biphenyl]-2-carbonitrile (134 g) is added to 550 ml of 10% aqueous solution of sodium hydroxide at 25°C to 30°C. 2-butyl-l,3-diazaspiro [4,4]nonan-4-one(100g) in 1200 ml of acetone is added to the above reaction mixture. The reaction mixture is maintained at 45°C to 55°C for 5 hrs, acetone is removed under vacuum, the residue is dissolved in 1000 ml of ethyl acetate, separated the layers, organic layer is washed with 250 ml of water followed by 1000 ml of IN sodium hydroxide solution and dried over sodium sulphate. Ethyl acetate is distilled off under vacuum at temperature below 60°C and the obtained residue is crystallized from 100 ml of acetonitrile to get 140g of the title product (73.8%), HPLC purity: 99.5% Example 2: Preparation of 2-butyl-3- [2'-(triphenylmethyItetrazol-5-yI)-biphenyl-4-yImethyI]-l,3-diazaspiro [4»4]-non-l-ene-4-one 5-(4'-bromomethyl-biphen-2-yl)-l-trityl-lH-tetrazole (57.3 g) is added to 110 ml of 10% aqueous solution of sodium hydroxide at 25°C to 30°C. 2-butyM,3-diazaspiro [4,4] non-an-4-one(20 g) in 240 ml of acetone is added to the above reaction mixture and maintained at 45 C for 6 hrs. Acetone is removed by distillation under vacuum, residue is dissolved in 200 ml of ethyl acetate, allowed to settle, separated the layers, organic layer is washed with 50 ml of water, 200 ml of sodium hydroxide solution and dried over sodium sulphate. Ethyl acetate is removed by distillation under vacuum and the residue obtained is crystallized from acetonitrile to afford 32.4g(47%) of 2-butyl-3-[2'-(triphenylmethyltetrazol-5-yl)-biphenyl-4-ylmethyl]-l,3-diazaspiro[4,4]-non-l-ene-4-one. Purity by HPLC: 98.5%. Example 3: Preparation of 4'-[[2-butyl-4-oxo-l, 3-diazaspiro [4,4] non-l-ene-3-yl] methyl] [1,1 '-biphenylJ-2-carbonitrile 4'-(bromomethyl)[l,l-biphenyl]-2-carbonitrile (13.4 g) is added to 50 ml of 10% aqueous solution of potassium hydroxide at 25°C to 30°C. A solution of 10 g of 2-butyl-l,3-diazaspiro [4,4]nonan-4-one in 120 ml of tetrahydrofuran is added to the above reaction mixture. Temperature of the reaction mass is raised and maintained at reflux temperature for 9 hrs. Tetrahydrofuran is removed by distillation under vacuum, and the residue is dissolved in 100 ml of ethyl acetate. Reaction mixture is allowed to settle and the layers are separated. Ethyl acetate layer is washed with water followed by sodium hydroxide solution and dried over sodium sulphate. Ethyl acetate is distilled under vacuum and the residue is crystallized from acetonitrile to get 11.2g (Yield: 68%) of the title product. Purity by HPLC: 99.6% Example 4: Preparation of 4'-[[2-butyl-4-oxo-l, 3-diazaspiro [4,4] non-l-ene-3-yl] methyl-1,1-biphenyl}-2-carbonitrile 4'-(bromomethyl)[l,l-biphenyl]-2-carbonitrile (27 g) is added tollO ml of 10% aqueous solution of potassium hydroxide at 25°C -30°C. A solution of 20 g of 2-butyl-l,3-diazaspiro [4,4]nonan-4-one in 240 ml of acetonitrile is added to the above reaction mixture. Temperature of the reaction mass is raised and maintained at 45°C for 4 hrs. Acetonitrile is partially (-65%) removed under vacuum, cooled to 0°C and filtered toget 24g (62.3%) of the title product, HPLC purity: 99.6 % We claim: 1. A process for the preparation of N-substituted l-[(biphenyl-4-yl) methyl-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one comprising of the steps - Adding 4'-(bromomethyl)[l,r-biphenyl] derivative to an aqueous solution of inorganic base - Adding 2-butyl-l, 3-diazaspiro [4,4] nonan-4-one to the above reaction mixture - Maintaining the reaction mixture at temperature of 25°C to reflux temperature - Removing the solvent - Dissolving the obtained residue in water-immiscible organic solvent - Washing the reaction mixture with water and sodium hydroxide solution - Drying the organic layer over desiccant - Removing the solvent to get residue - Crystallizing the residue from acetonitrile 2. The process as claimed in claim 1, wherein the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and mixtures thereof. 3. The process as claimed in claim 1, wherein the 2-butyl-l, 3-diazaspiro [4,4] nonan-4-one is dissolved in water miscible organic solvent. 4. The process as claimed in claim 3, wherein the water miscible organic solvent is selected from acetone, acetonitrile, alkanols, 1,4-dioxane and mixtures thereof 5. The process as claimed in claim 4, wherein the preferred water miscible organic solvent is acetone or acetonitrile. 6. The process as claimed in claim 1, wherein the solvent is removed under vacuum. 7. The process as claimed in claim 1, wherein the water-immiscible organic solvent is selected from chloroform, methylene chloride, ethyl acetate and mixtures thereof 8. The process as claimed in claim 1, wherein desiccant is sodium sulphate, magnesium sulphate

Documents:

566-che-2004 correspondence others 12-04-2011.pdf

566-che-2004 form-1 12-04-2011.pdf

566-che-2004 form-13 30-11-2010.pdf

566-che-2004-abstract.pdf

566-che-2004-claims duplicate.pdf

566-che-2004-claims original.pdf

566-che-2004-correspondnece-others.pdf

566-che-2004-correspondnece-po.pdf

566-che-2004-description(complete) duplicate.pdf

566-che-2004-description(complete) original.pdf

566-che-2004-form 1.pdf

566-che-2004-form 13.pdf

566-che-2004-form 3.pdf