Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF VALSARTAN AND ITS INTERMEDIATES
Abstract	We claim, 1. A process for the preparation of valsartan of formula (I) comprising the steps of: i) reacting a compound of formula (Ha) wherein X is any halogen, with a compound of formula (IIb) or a salt thereof, wherein R represents carboxy protecting group, characterized in that the reaction is carried out in a heterogeneous solvent mixture comprising of water and non-polar hydrocarbon solvent, in presence of a basic material and optionally in presence of catalyst to obtain a compound of Formula II; ii) acylating said compound of formula (II) or a salt thereof with a compound of formula (IIc) in presence of an organic base characterized in that the reaction is carried out in non-polar hydrocarbon solvent to obtain a compound of Formula HI; (III) iii) reacting said compound (III) with tributyl tin azide in an aromatic solvent and isolating benzyl valsartan of formula IV characterized in that the benzyl valsartan is further purified from a mixture of solvents to get benzyl valsartan substantially free of organotin impurity content; and iv) hydrogenating the benzyl valsartan substantially free of organotin content in presence of 2.5 to 5.0 % wt/wt of palladium -charcoal catalyst relative to starting benzyl valsartan to obtain valsartan.

Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF VALSARTAN AND ITS INTERMEDIATES

Abstract

We claim, 1. A process for the preparation of valsartan of formula (I) comprising the steps of: i) reacting a compound of formula (Ha) wherein X is any halogen, with a compound of formula (IIb) or a salt thereof, wherein R represents carboxy protecting group, characterized in that the reaction is carried out in a heterogeneous solvent mixture comprising of water and non-polar hydrocarbon solvent, in presence of a basic material and optionally in presence of catalyst to obtain a compound of Formula II; ii) acylating said compound of formula (II) or a salt thereof with a compound of formula (IIc) in presence of an organic base characterized in that the reaction is carried out in non-polar hydrocarbon solvent to obtain a compound of Formula HI; (III) iii) reacting said compound (III) with tributyl tin azide in an aromatic solvent and isolating benzyl valsartan of formula IV characterized in that the benzyl valsartan is further purified from a mixture of solvents to get benzyl valsartan substantially free of organotin impurity content; and iv) hydrogenating the benzyl valsartan substantially free of organotin content in presence of 2.5 to 5.0 % wt/wt of palladium -charcoal catalyst relative to starting benzyl valsartan to obtain valsartan.

Full Text	FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION: "An improved process for the preparation of Valsartan and its intermediates" 2. APPLICANT: (a) NAME: IPCA LABORATORIES LIMITED (b) NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India 3.PREAMBLE TO THE DESCRIPTION: The following specification particularly describes the invention and the manner in which it is to be performed ORIGINAL 490/MUM/2008 GRANTED 6-7-2007 22 SEP 2005 Field of invention : The present invention relates to an improved process for the preparation of a known pharmaceutical agent, Valsartan, and its intermediates in substantially pure enantiomeric form. Background of the invention: (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine commonly known as Valsartan has the following structure (Formula I): (I) Valsartan is a member of the class of agents termed angiotensin-II (AT) receptor antagonists having effective anti-hypertensive activity with an excellent profile of safety and tolerability. Activation of AT receptors in the outer membrane of vascular smooth muscle cells of the heart and arteries causes the tissues to constrict. AT-I receptors are activated by an octa-peptide, angiotensin-II. Angiotensin-II helps to maintain constant blood pressure despite fluctuations in a person's state of hydration, sodium intake and other physiological variables. Angiotensin-II also performs the regulatory tasks of inhibiting excretion of sodium by the kidneys, inhibiting nor-ephedrin reuptake and stimulating aldosterone biosynthesis. By inhibiting angiotensin-II binding to AT receptors, valsartan disrupts the vasoconstriction mediated by AT receptors. Valsartan is therefore a non-peptide angiotensin-II antagonist, inhibits the actions of angiotensin-II on its receptors, thus preventing the increase of blood pressure produced by the hormone-receptor interactions. Hence it is used in the treatment of cardiovascular complaints such as hypertension and heart failure. Comparative trial studies have shown that valsartan is as effective as angiotensin-converting enzyme, (ACE) inhibitors, calcium-channel blockers and a-blockers, and is generally better tolerated. Valsartan is marketed as the free acid under the trade name DIOVAN, however, its combination with diuretics, such as hydrochlorothiazide have specific advantage as anti-hypertensive agent. The synthesis of Valsartan and its intermediates of formula II, III and IV are reported in patent (US patent no. 5,399,578) and Bioorganic & Medicinal Chemistry Letters, vol. 4, pp 29-34,1994, via the following method as shown in Scheme I: \-J \-J Scheme I Although the process appears to be practical but involves many disadvantages from the point of view of purity/yield of valsartan and its intermediates obtained by following the method outlined in '578 patent. The major problems are incomplete reactions, contamination of valsartan with a number of impurities or starting material/intermediates and lower chiral purity of valsartan obtained. One of the major disadvantage is the incomplete reaction of (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester or salts thereof with valeroyl chloride in chlorinated solvents in the preparation of (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester of formula III and thus results in contamination of compound II. This impurity in turn is carried forward in subsequent reaction steps and results in valsartan of low purity. A further disadvantage of prior method is the contamination of organotin impurity in the penultimate intermediate of valsartan namely, (S)-N-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester of the formula IV (benzyl valsartan), during the tetrazole formation of formula III. An effective purification or means to remove the organotin by-product is not described or disclosed in '578 patent. As a result the catalyst (palladium -charcoal) gets poisoned in the presence of organotin impurity during the debenzylation of benzyl valsartan (IV) and necessitates a very high loading of palladium- charcoal for completing the reaction. The prior processes employ solvents like DMF during the preparation of compound of formula II and formula III and the need of the hour is the more greener chemistry, environmental friendly solvents and conditions etc. Yet another problem is the racemization of valsartan or its intermediates during the reaction conditions or purification processes as described in '578 patent. Racemization herein means the process of a relatively pure substance becoming a mixture of enantiomeric forms. Valsartan is used in the enantiomerically pure (S)-N-[(2'-(lH- tetrazol-5-yl)biphenyl-4-yl)methyl]-N-valeroyl-(L)-valine form in pharmaceutical compositions. Thus there is a need in the art for an improved and cost-effective synthetic process for the preparation of valsartan and precursors thereof in its enantiomerically pure form. Objects of the invention: It is an objective of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art or to provide a useful alternative. It is an object of the present invention in its preferred form to provide an industrial process for the preparation of valsartan substantially in its pure enantiomeric form. Other objectives of this invention include establishment of suitable purification methods to remove the organo-tin by-product from benzyl valsartan, overcome the incomplete reactions during the intermediates preparation, speeding-up the reactions and providing suitable environmentally friendly solvents in the process for Valsartan. Summary of the invention: Accordingly, the present invention relates to an improved method for the preparation of valsartan having an enantiomeric purity of at least 99.8% In one embodiment of the present invention, the intermediate compound of Formula II is prepared by reacting a compound of Formula (Ha) with compound of Formula (IIb) in a heterogeneous solvent system/medium, preferably in a mixture of water and an organic solvent, in presence of an inorganic base and isolating it as hydrochloride salt. The said reaction may be optionally performed in presence of a catalyst. In another embodiment of the present invention, the compound II is acylated with valeroyl chloride in presence of an organic base in solvents selected from non-polar solvents like toluene, xylene etc. till completion of the starting compound II to at least 99.8% in a short period of time. In yet another embodiment of the present invention benzyl valsartan substantially free of the organotin impurity is provided by a reaction of Compound III with tributyl tin azide in toluene or xylene and purifying the isolated crude benzyl valsartan contaminated with organotin impurity from a first solvent that is a ternary solvent mixture, characterized by combination of hydrophilic organic solvent selected from C1 to C4 alcohol, non-polar organic solvent like hexane or toluene or the like and water, followed by crystallizing from a second solvent such as a non-polar organic solvent or a polar aprotic solvent or mixtures thereof. In a further aspect, the present invention provides a process for debenzylation of benzyl valsartan substantially free of organotin impurity using palladium carbon in significantly lower catalyst loading at ambient temperature in a hydrophilic organic solvent selected from C1 to C4 alcohol followed by crystallizing valsartan of enantiomeric purity of at least 99.8 % from solvents mixture such as ethyl acetate and hexane or ethyl acetate and ether at a temperature below 60°C. Detailed description of the invention: The present invention thus provides a process for preparation of valsartan and its intermediates in substantially pure enantiomeric form. The details of the present process are described herein. X is any halogen. More preferable halogen is bromine. In the first step, the compound of the general Formula Ha is reacted with compound of general formula IIb in presence of a base and optionally in presence of a catalyst. In a preferred embodiment of the present invention the above reaction step is carried out in a heterogeneous solvent mixture comprising water and a non-polar hydrocarbon solvent. In the general formula Ha: X is any halogen. More preferable halogen is bromine. In the general formula lib or a salt thereof: R represents any carboxyl protecting group and however the preferred carboxyl protecting group is methyl or benzyl group. In the reaction the compound lib may be used as its acid salt preferably hydrochloric acid salt or p-toluene sulphonic acid salt and more preferably p-toluene sulphonic acid salt. If an acid salt is employed in the reaction an excess amount of base is used, which is required to neutralize the salt to free compound IIb. The heterogeneous solvent mixture comprises a non-noxious solvent water and an organic solvent preferably a hydrocarbon solvent such as toluene, xylene. The organic solvent and water mixture comprises, based on the total volume of the solvent mixture, from about 40% to 80% of non-polar organic solvent and about 60% to 20% of water. Preferably the reaction is carried out in a mixture of non-polar hydrocarbon solvent and water comprising, based on the total volume of the solvent mixture, from about 40% to 60% of non-polar hydrocarbon solvent and about 60% to 40% of water. As described above the preferred non-polar hydrocarbon solvents are selected from C6 -C9 aromatic hydrocarbon or C5 - C8 aliphatic hydrocarbon or C5 - C8 alicyclic hydrocarbon. Other hydrocarbons useful in the practice of the present invention will be apparent to the skilled artesian. The preferred non-polar solvent is selected from, but is not limited to, toluene, xylene, hexane, cyclohexane or mixtures thereof. The most preferred non-polar solvent is toluene. The basic material used in the reaction is an inorganic base such as carbonate or bicarbonate salt of an alkali metal and preferably the alkali metal salt is sodium carbonate, potassium carbonate or sodium bicarbonate. The reaction may optionally be carried out in the presence of a catalyst. Preferred catalyst is selected form potassium iodide, sodium iodide, or a phase-transfer catalyst such as tetrabutyl ammonium bromide, tetrabutyl ammonium chloride or a combination of phase-transfer catalyst and sodium/potassium iodide. The reaction is carried out at a temperature from an ambient temp to the reflux temperature of the reaction mixture. More preferably heat is used to effect the completion of reaction at a temperature of about 40°C - 60°C and the reaction completes in a period of about 20 hours to 30 hours. On completion of the reaction, the intermediate compound II is isolated from the reaction mixture by phase separation & water washing, and acidification of the organic layer. The reaction product (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester of formula II, gets separated out in the form of its hydrochloride salt after acidification of the reaction mixture using hydrochloric acid, gaseous hydrochloric acid or aqueous hydrochloric acid to a pH of 1-4. The precipitated (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride shows a purity above 95% with an yield of about 85%. The (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride is used as such in subsequent reaction or may be isolated as its free base by neutralization procedure known in the art. In a second step of the present inventi on, the hydrochloride salt of (S)-N-[(2'- cyanobiphenyl-4-yI)methyl]-(L)-valine benzyl ester (Formula II) is reacted with a compound of formula IIe as shown below in presence of a base like diisopropylethylamine, v=/ (II) or a salt thereof with a compound of formula (lie) ,0 According to the present invention the above process step, reaction of (S)-N-[(2'-cyano-biphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride with compound lie, is carried out in a non-polar hydrocarbon solvent. The preferred non-polar solvent is selected from C6 - C9 aromatic hydrocarbon or C5 - C8 aliphatic hydrocarbon or C5 - C8 alicyclic hydrocarbon and is preferably toluene. The reaction is carried out at a temperature between 0°C to the reflux temperature and preferably between 20°C to the reflux temperature of the solvent. Most preferably the reaction is carried out between 25°C - 35°C and the reaction completes in a span of 1 to 5 hours. In the third step, the cyano group in compound of formula III is converted into tetrazole ring system by reaction with tributyltin azide to produce the penultimate intermediate of valsartan called benzyl valsartan. Usually the tributyltin azide is added in three lots. Toluene is used as solvent and the reaction is effected at reflux temperature. In a preferred embodiment of the present invention the stage III product on water washings is directly employed in the tetrazole formation when the solvent is toluene or xylene. After the completion of tetrazole formation, the benzyl valsartan is released from the tributyl tin complex by passing dry hydrochloric acid gas to the reaction mixture, toluene is decanted off and the residue is taken in water immiscible solvent, washed with water till free of acid. The compound of formula IV is isolated as oil in crude form. Generally the second step and third step is carried out insitu without isolating the product of second step. The present invention provides a purification method for effective removal of the organotin impurity from benzyl valsartan of the formula (IV) The purification process of the present invention includes a first crystallization of benzyl valsartan from a ternary solvent mixture comprises a hydrophilic organic solvent, a non-polar organic solvent and water, and a second crystallization from a polar aprotic solvent or non-polar organic solvent or mixtures thereof. The hydrophilic organic solvents used in the ternary solvent mixture in the first purification are selected from C1 to C4 alcohols especially isopropanol. The non-polar organic solvents are selected from hydrocarbon solvents like hexane, toluene, cyclohexane or the like. The composition of the ternary mixture is as follows: the ratio of hydrophilic organic solvent to inert non-polar organic solvent is in the range of about 1:0.5 to 1:100 parts by weight and preferably is in the range of about 1:0.5 to 1:25 parts by weight and more preferably is in the range of about 1:0.5 to 1:10 parts by weight, on the basis of 1 part by weight of compound of formula IV. The ratio of water to combination of hydrophilic organic solvent and inert non-polar organic solvent is in the range of about 0.5: 1 to 10:1 parts by weight and preferably is in the range of about 0.5:1 to 5:1 parts by weight, on the basis of 1 part by weight of compound of formula IV. In a preferred form, water is added to a pre-formed solution of compound of formula IV (Benzyl valsartan) in a mixture of hydrophilic organic solvent and non-polar organic solvent between 0°C to reflux temperature. Preferably the addition is carried out between 25 °C - 35°C and the benzyl valsartan precipitates out of the solution. The precipitated compound of formula IV is isolated by filtration or other conventional means at ambient temperature or by further cooling to 0°C. According to the present invention, benzyl valsartan is further purified from a second solvent, preferably the non-polar organic solvent or polar aprotic solvent or mixtures thereof, to obtain benzyl valsartan substantially free of organotin impurity in high enantiomeric purity. The non-polar organic solvent is selected from C6 - C9 aromatic hydrocarbon, C5 - C8 aliphatic hydrocarbon or C5 - C8 alicyclic hydrocarbon. The non-polar organic solvents are selected from hydrocarbon solvents like hexane, toluene or the like and the inert polar aprotic solvent is ethyl acetate. In the process of purification the non-polar organic solvent is added to a solution of benzyl valsartan in polar aprotic solvent between 0°C to reflux temperature. Preferably the addition of non-polar organic solvent is carried out between 25°C - 35°C to precipitate benzyl valsartan substantially free of organotin impurity. The combination of non-polar organic solvent to ethyl acetate preferably has a ratio in which ethyl acetate to the non-polar organic solvent is in the range of about 1:0 to 1:100 parts by weight and preferably is in the range of about 1:0 to 1:50 parts by weight and more preferably is in the range of about 1:0 to 1:25 parts by weight, on the basis of 1 part by weight of compound of formula IV. The precipitated benzyl valsartan can be separated from the mixture by conventional means such as filtration and can be optionally dried at a temperature below 60°C. The benzyl valsartan obtained above is subjected to hydrogenation in presence of palladium-charcoal to obtain valsartan. The present invention is characterized by a lower loading of costly palladium-charcoal catalyst in the debenzylation of benzyl valsartan substantially free of organotin impurity. In the presence of organotin impurity, the catalyst gets poisoned and looses the activity and thus necessitates a heavy loading of costly palladium-charcoal catalyst in the prior art. The present invention has reduced the palladium-charcoal quantity by about 70% with respect to the prior art processes. After the completion of the reaction, the product was filtered, concentrated and solution of valsartan in an aqueous basic solution is prepared. The aqueous basic solution may be that of an alkali metal or alkaline earth metal salt such as sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide or potassium hydroxide. The aqueous layer is washed with chlorinated solvent such as methylene dichloride or ethylene dichloride. The aqueous solution is then rendered acidic using aqueous acidic solutions of inorganic acids such as hydrochloric acid, sulfuric acid or acetic acid. Precipitated valsartan is then extracted using an organic solvent such as ethyl acetate or isobutyl methyl ketone or methyl propyl ketone. The organic phase is concentrated under reduced pressure to dryness; residue is suspended / slurry washed with hydrocarbon solvent such as toluene, hexane, cyclohexane, a combination of hydrocarbon solvent with ethyl acetate or diisopropyl ether or a mixture thereof and valsartan can be separated from the mixture by decanting, filtering, centrifuging or using other similar processing methods of isolation of solids from liquids known to a person skilled in the art, or any combination of such separation methods and is optionally followed by a wash with water. Valsartan after acidification and extraction in above said solvent can also be isolated by slurryfication, at a temperature below 60°C, from premix solvent mixtures such as ethyl acetate-hexane or ethyl acetate-diisopropylether optionally in presence of water. Valsartan can be separated from the mixture by decanting, filtering, centrifuging or using other similar processing methods of isolation of solids from liquids known to a person skilled in the art, or any combination of such separation methods and is optionally followed by a wash with water. Isolated valsartan is dried, at a temperature below 60°C, by air drying, vacuum drying or fluidized bed drying or using other similar drying methods of solids known to a person skilled in the art, or any combination of such drying methods. The temperature of reaction as well as isolation and drying is crucial for getting higher enantiomeric excess as at higher temperature valsartan tends to racemize. The valsartan obtained by following the process of the present invention has a purity of at least 99.7% and the R-isomer content is less than 0.10%. This drastic yield and purity improvement caused by the above-described variations thus lead to an efficient and commercially acceptable synthetic process for the preparation of valsartan. This higher enantiomeric purity and yield starting from compound of Formula II constitutes a considerable technical advance with respect to the process described in US 5,399,578 patent. The invention is explained in more detail in the following working examples. The examples, which illustrate improvement in the method according to the invention, have a purely illustrative character and do not limit the extent of the invention in any respect. Example 1 (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride 4-bromomethyl-2'-cyanobiphenyl (15gm, 0.055 mol), L-valine benzyl ester tosylate (20.9 gm, 0.055 mol), potassium carbonate (21 gm, 0.152 mol), potassium iodide (0.21 gm) were heated to 50-55°C in toluene (63 ml) and water (63 ml) for 25 hours. After cooling down, the two phases separated out. The organic layer water washed (2 x 50 ml) and acidified with hydrochloric acid to pH 1-2, upon which the product crystallized out; 17.9 gm (75%). The product purity was about 97%. Example 2 (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride 4-bromomethyl-2'-cyanobiphenyl (15gm, 0.055 mol), L-valine benzyl ester tosylate (20.9 gm, 0.055 mol), potassium carbonate (21 gm, 0.152 mol), tetrabutyl ammonium bromide (0.21 gm) were heated to 50-55°C in cyclohexane (50 ml) and water (75 ml) for 25 hours. After cooling down, the two phases separated out. The organic layer water washed and acidified with hydrochloric acid to pH 1-2, upon which the product crystallized out; 12.4 gm (72.11%). The product purity was about 96%. Example 3 (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride 4-bromomethyl-2'-cyanobiphenyl (15gm, 0.055 mol), L-valine benzyl ester tosylate (20.9 gm, 0.055 mol), sodium bicarbonate (21 gm, 0.152 mol), tetrabutyl ammonium bromide (0.21 gm) were heated to 50-55°C in toluene (63 ml) and water (63 ml) for 30 hours. After cooling down, the two phases separated out. The organic layer water washed and acidified with hydrochloric acid to pH 1-2, upon which the product crystallized out; 16.7 gm (70%). The product purity was about 92%. Example 4 (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride 4-bromomethyl-2'-cyanobiphenyl (15gm, 0.055 mol), L-valine benzyl ester tosylate (20.9 gm, 0.055 mol), potassium carbonate (21 gm, 0.152 mol), tetrabutyl ammonium bromide (0.21 gm) were heated to 50-55°C in xylene (63 ml) and water (63 ml) for 25 hours. After cooling down, the two phases separated out. The organic layer water washed and acidified with hydrochloric acid to pH 1-2, upon which the product crystallized out; 17.4 gm (73%). The product purity was about 97%. Example 5 (S)-N-[(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine benzyl ester hydrochloride 4-bromomethyl-2'-cyanobiphenyl (15gm, 0.055 mol), L-valine benzyl ester tosylate (20.9 gm, 0.055 mol), potassium carbonate (21 gm, 0.152 mol), tetrabutyl ammonium bromide (0.21 gm) and potassium iodide (0.21 gm) were heated to 50-55°C in toluene (63 ml) and water (63 ml) for 25 hours. After cooling down, the two phases separated out. The organic layer water washed and acidified with hydrochloric acid to pH 1-2, upon which the product crystallized out; 21.6 gm (90%). The product purity was about 97%. Example 6 (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride 4-bromomethyl-2'-cyanobiphenyl (15gm, 0.055 mol), L-valine benzyl ester tosylate (20.9 gm, 0.055 mol), potassium carbonate (21 gm, 0.152 mol) were heated to 50-55°C in toluene (63 ml) and water (63 ml) for 25 hours. After cooling down, the two phases separated out. The organic layer water washed and acidified with hydrochloric acid to pH 1-2, upon which the product crystallized out; 17.2 gm (72%). The product purity was about 96%. Example 7 (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride 4-bromomethyl-2'-cyanobiphenyl (4.2 kg, 0.0154 mol), L-valine benzyl ester tosylate (5.85 kg, 0.0154 mol), potassium carbonate (5.88 kg, 0.0426 mol), potassium iodide (0.059 kg) were heated to 50-55°C in toluene (17.6 It) and water (17.6 It) for 25 hours. After cooling down, the two phases separated out. The organic layer water washed (2 x 14 It) and acidified with hydrochloric acid to pH 1-2, upon which the product crystallized out; 5.04 kg (75.4%). The product purity was about 97%. Example 8 (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester To sodium bicarbonate (65 gm, 0.774 mol) in water (800 ml) and toluene (400 ml) was added (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride (210 gm, 0.483 mol) at 25°C. Stirred for an hour, layers separated and the toluene layer was washed with brine solution. It was dried over sodium sulfate. To the dried toluene layer containing (S)-N-[(2'-cyano biphenyl-4-yl)methyl]-(L)-valine benzyl ester was added N,N-diisopropylethylamine (101.8 gm, 0.786 mol) at 25°C. It was cooled down to 20°C and valeroyl chloride (80 gm, 0.664 mol) was added over a period of about 30 minutes. After the completion of reaction by TLC check, 50 ml water was added and further stirred for 30 minutes. Layers were separated and to the organic layer at 0°C was added IN hydrochloric acid solution till pH was about 1-3, stirred for 30 minutes and layers separated. To the organic layer added 10% sodium bicarbonate solution till pH of reaction mass was about 7-8. Layers separated and organic layer washed with 200 ml water and then with 200 ml brine solution. The organic layer evaporated, yielding 228 gm (98%) brownish oily substance. HPLC purity 96%. Example 9 (S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine To the dried toluene layer ((Solution B) as described in part b mentioned below)) was added; sodium azide (70 gm, 1.08 mol) and tibutyl tin chloride (350 gm, 1.07 mol). The reaction mass was heated to reflux. After about 20 hrs 2nd lot of sodium azide (10 gm, 0.154 mol) and tibutyl tin chloride (50 gm, 0.154 mol) was added. The reflux further continued for 20-24 hrs. After the completion of reaction by TLC check, it was cooled down to about 15°C and dry hydrochloric acid gas passed through the toluene layer till the decolorisation of toluene was observed. Toluene layer was decanted off and the residue washed with 100 ml of toluene. The residue was partitioned between methylene chloride and 10% sodium bicarbonate solution and stirred at 25-30°C for 30 minutes. Layers separated, organic layer washed with brine solution and dried over sodium sulfate. The organic layer evaporated, yielding 240 gm brownish oil. HPLC assay 91%. 23 gms of above oil was taken in 40 ml IPA and heated to get clear solution. To the reaction mass was added 200 ml hexane. It was further cooled to about 10-20°C and 250 ml water added in about 60 minutes. It was further stirred at 25-30°C for 60 minutes and filtered; 18 gm (78%). MP 106-108°C; HPLC assay 93-96%. Solution B can be prepared as follows: a) (S)-N-[(2'-cyano biphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride 4-bromomethyl-2'-cyanobiphenyl (15gm, 0.055 mol), L-valine benzyl ester tosylate (20.9 gm, 0.055 mol), potassium carbonate (21 gm, 0.152 mol), potassium iodide (0.21 gm) were heated to 50-55°C in toluene (63 ml) and water (63 ml) for 25 hours. After cooling down, the two phases separated out. The organic layer water washed (2 x 50 ml) and acidified with hydrochloric acid to pH 1-2, upon which the product crystallized out; 17.9 gm (75%). The product purity was about 97%. b) (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester. To sodium bicarbonate (65 gm, 0.774 mol) in water (800 ml) and toluene (400 ml) was added (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride (210 gm, 0.483 mol) at 25°C. Stirred for an hour. Layers separated and the toluene layer dried over sodium sulfate. To the dried toluene layer containing (S)-N-[(2'-cyano biphenyl-4-yl)methyl]-(L)-valine benzyl ester was added N,N-diisopropylethylamine (101.8 gm, 0.786 mol) at 25°C. It was cooled down to 15°C and valeryl chloride (80 gm, 0.664 mol) was added over a period of about 60 minutes. After the completion of reaction by TLC check, 100 ml water was added and further stirred for 30 minutes. Layers were separated and to the organic layer at 10°C was added IN hydrochloric acid solution till pH was about 1-3, stirred for 30 minutes and layers separated. To the organic layer added 10% sodium bicarbonate solution till pH of reaction mass was 7-8. Layers separated and organic layer washed with 200 ml water and then with 200 ml brine solution. The organic layer dried using sodium sulfate. The dried toluene layer (Solution B) was further used as such. Example 10 (S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)- biphenyl-4-ylmethyl] -amine Using the toluene layer from part-a the title compound was prepared analogously to Example 9. 5 gms of the above solid was taken in 15 ml Toluene, heated to get clear solution and stirred at ambient temperature and filtered; 4 gms (80%). MP 115.7-115.8°C; HPLC/ assay 99.54%. The starting material can be prepared, for example, as follows: a) (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester To sodium bicarbonate (65 gm, 0.774 mol) in water (800 ml) and toluene (400 ml) was added (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride (210 gm, 0.483 mol) at 25°C. Stirred for an hour. Layers separated and the toluene layer dried over sodium sulfate. To the dried toluene layer containing (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester was added N,N-diisopropylethylamine (101.8 gm, 0.786 mol) at 25°C. It was cooled down to 15°C and valeryl chloride (80 gm, 0.664 mol) was added over a period of about 60 minutes and further processed analogously to Example 9b. Example 11 (S)-N-( 1 -benzyloxycarbonyl-2-methyl-prop-1 -yl)-N-pentanoyl-N- [2' -(1 H-tetrazol-5 -yl)-biphenyl-4-ylmethyl] -amine Using the toluene layer from part-a the title compound was prepared analogously to Example 9. 5 gms of the above solid was taken in 10 ml ethyl acetate and heated to get clear solution. Added 20 ml hexane and cooled down to 25-30°C upon which the product crystallized out; 3.5 gm (70%). MP 115.2-115.8°C; HPLC assayl00.15%. The starting material can be prepared, for example, as follows: a) (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester Starting with 210 gms of (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride the title compound was prepared analogously to Example 9b. Example 12 (S)-N-( 1 -benzyloxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N-[2' -(1 H-tetrazol-5 -yl)-biphenyl-4-ylmethyl]-amine Using the toluene layer from part-a the title compound was prepared analogously to Example 9. 5 gms of the above solid was taken in 15 ml toluene and heated to get clear solution. Added 10 ml hexane and cooled down to ambient temperature upon which the product crystallized out; 4.5 gm (90%). MP 115.9-116°C, HPLC assaylOO.46%. The starting material can be prepared, for example, as follows: a) (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester Starting with 210 gms of (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride the title compound was prepared analogously to Example 9b. Example 13 (S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)- biphenyl-4-ylmethyl]-amine Using the toluene layer from part-a the title compound was prepared analogously to Example 9. 1 kgs of the above solid was taken in 2 It ethyl acetate and heated to get clear solution. Added 4 It hexane and cooled down to 25-30°C upon which the product crystallized out; 3.5 kg (70%). MP 115.2-115.8°C; HPLC assayl00.15%. The starting material can be prepared, for example, as follows: a) (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester Starting with 2.1 kgs of (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride the title compound was prepared analogously to Example 9b. Example 14 (S)-N-(l -Carboxy-2-methyl-prop-1 -yl)-N-pentanoyl-N-[2' -(1 H-tetrazol-5-yl)-biphenyl-4- ylmethyl]-amine. A solution of 50 gm (S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-pentanoyl-N- [2'-(lH-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine in 500 ml methanol was hydrogenated at room temperature with the addition of 2.5 gm Pd-C (5%) till the completion of reaction. The crude valsartan was obtained by filtration and evaporation of the solvent. It was partitioned between 500 ml of 10% sodium bicarbonate solution and 200 ml MDC. The aqueous phase was separated and rendered acidic, and the title compound isolated by extraction with ethyl acetate. It was crystallized from mixture of ethyl acetate and hexane; 34 gm (82%). HPLC 99.8% and R-isomer 0.07%. Example 15 (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)-biphenyl-4- ylmethyl]-amine. A solution of 50 gm (S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-pentanoyl-N- [2'-(lH-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine in 300 ml methanol was hydrogenated at room temperature with the addition of 1.25 gm Pd-C (5%) and further proceeded analogously to example 14. It was crystallized from mixture of ethyl acetate and di- isopropyl ether; 29 gm (70%). HPLC 99.83% and R-isomer 0.03%. Example 16 A solution of 50 gm (S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine in 500 ml methanol was hydrogenated at room temperature with the addition of 1.25 gm Pd-C (5%) till the completion of reaction. The crude valsartan was obtained by filtration and evaporation of the solvent. The residue was partitioned between 500 ml of 10% sodium bicarbonate solution and 200 ml MDC. The aqueous phase was separated and rendered acidic, and the title compound isolated by extraction with ethyl acetate. The organic phase was distilled under reduced pressure to dryness, the residue was suspended in a mixture of ethyl acetate:hexane at ambient temperature, filtered, washed with water and dried; 34 gm (82%). HPLC 99.8% and R-isomer 0.05%. Example 17 A solution of 50 gm (S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-pentanoyl-N- [2'-(lH-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine in 500 ml methanol was hydrogenated at room temperature with the addition of 2.5 gm Pd-C (5%) till the completion of reaction. The crude valsartan was obtained by filtration and evaporation of the solvent. It was partitioned between 500 ml of 10% sodium bicarbonate solution and 200 ml MDC. The aqueous phase was separated and rendered acidic, and the title compound was isolated by extraction with ethyl acetate, The organic phase was distilled under reduced pressure to dryness, slurried in a mixture of ethyl acetate:hexane:water (ratio 2:5:1), filtered and dried; 34 gm (82%). HPLC 99.8% and R-isomer 0.02%. Comparative Example 1 (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester 6.2 gm (15.5 mmol) of (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester and 8.0 ml N,N-diisopropylethylamine, dissolved in 50 ml of methylene chloride, are treated with 2.3 ml of valeryl chloride with stirring. The reaction mixture was stirred at room temperature for 20-25 hours until starting amine can no longer be detected by TLC. After evaporating in a water jet vacuum, the reaction mixture was partitioned between 82 ml water and 826 ml ethyl acetate. The organic phase was washed successively with 40 ml each of 2N hydrochloric acid, saturated NaHCO3 solution and brine, dried over magnesium sulfate and evaporated in vacuum. The title compound obtained as brown oil. HPLC purity 72%. Comparative Example 2 (S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)-biphenyl-4-ylmethyl] -amine. 6.6 gm (13.6 mmol) of (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester and 6.0 gm (18 mmol) of tributyltin azide in 75 ml of o-xylene are heated to boiling with stirring for 48 hours. After 24 hours, 2.0 gm of tributyltin azide are added. After cooling, the solution was diluted with about 125 ml of toluene, treatd with 110 ml IN potassium hydroxide solution and stirred for 20 minutes. The aqueous phase was separated and rendered acidic with IN hydrochloric acid solution, the product extracted in ethyl acetate. The title compound after evaporation of solvent was obtained as oil. HPLC assay 86-88%. We claim, 1. A process for the preparation of valsartan of formula (I) comprising the steps of: i) reacting a compound of formula (Ha) wherein X is any halogen, with a compound of formula (IIb) or a salt thereof, wherein R represents carboxy protecting group, characterized in that the reaction is carried out in a heterogeneous solvent mixture comprising of water and non-polar hydrocarbon solvent, in presence of a basic material and optionally in presence of catalyst to obtain a compound of Formula II; ii) acylating said compound of formula (II) or a salt thereof with a compound of formula (IIc) in presence of an organic base characterized in that the reaction is carried out in non-polar hydrocarbon solvent to obtain a compound of Formula HI; (III) iii) reacting said compound (III) with tributyl tin azide in an aromatic solvent and isolating benzyl valsartan of formula IV characterized in that the benzyl valsartan is further purified from a mixture of solvents to get benzyl valsartan substantially free of organotin impurity content; and iv) hydrogenating the benzyl valsartan substantially free of organotin content in presence of 2.5 to 5.0 % wt/wt of palladium -charcoal catalyst relative to starting benzyl valsartan to obtain valsartan. 2. The process as claimed in claim 1, wherein said heterogeneous solvent mixture of non-polar hydrocarbon solvent and water in step (i) comprising, based on the total volume of the solvent mixture, from about 40% to 60% of the non-polar hydrocarbon solvent and about 60% to 40% of water. 3. The process as claimed in claim 2, wherein the non-polar hydrocarbon solvent is toluene, xylene, hexane, cyclohexane or mixtures thereof. 4. The process as claimed in any one of the preceding claim, wherein the catalyst in step (i) is selected from potassium iodide, sodium iodide, or a phase-transfer catalyst such as tetrabutyl ammonium bromide, tetrabutyl ammonium chloride or a combination of phase-transfer catalyst and sodium/potassium iodide. 5. The process as claimed in claim 1, wherein step (iii) is carried out without isolating the compound of step (ii). 6. The process as claimed in claim 1 or 5, wherein benzyl Valsartan (IV) in step (iii) is purified first from a ternary solvent medium comprising a hydrophilic organic solvent, non-polar organic solvent and water, followed by crystallizing from a second solvent system comprising a non-polar organic solvent or a polar aprotic solvent or mixtures thereof. 7. The process as claimed in claim 6, wherein said ternary solvent mixture has hydrophilic organic solvent to non-polar organic solvent ratio in the range of about 1:0.5 to 1:100 parts, and hydrophilic organic solvent & non-polar organic solvent to water ratio is in the range of about 1:0.5 to 1:10 parts by weight relative to benzyl Valsartan. 8. The process as claimed in claim 7, wherein the hydrophilic organic solvent is selected from C1 to C4 alcohols. 9. The process as claimed in claim 8, wherein said alcohol is IP A. 10. The process as claimed in claim 6, wherein the second purification solvent system has polar aprotic solvent to non-polar organic solvent ratio in the range of about 1:0 to 1:100 parts by weight relative to benzyl valsartan. 11. The process as claimed in claim 6 or 10, wherein the non-polar organic solvent is selected from the group of C6 - C9 aromatic hydrocarbon or C5 - C8 aliphatic hydrocarbon or C5 - C8 alicyclic hydrocarbon. 12. The process as claimed in claim 11, wherein the non-polar organic solvent is toluene, hexane or mixtures thereof. 13. The process as claimed in claim 6 or 10, wherein said polar aprotic solvent is ethyl acetate. 14. A process as herein described in accompanying text, description and examples. Dated this 22nd day of September 2005 Dr. Gopakumar G. Nair Agent for the Applicant devices 39A & 39B. Fine particles of spent catalyst and coked adsorbent carried along with hydrocarbon vapors to the reactor 38 are separated using cyclones 40A & 40B.The diplegs of 39A, 39B, 40A & 40B are terminated close to spent catalyst and coked adsorbent bed interface in stripper cum separator 37. As described above, spent catalyst and coked adsorbent mixture collected in stripper cum separator 37 is separated in to two layers 62 & 63 and taken to respective regenerators 44, & 54 for regeneration/reactivation. The cycle of regeneration, feed contaminants removal, cracking reaction followed by gas-catalyst-adsorbent separation and then separation of spent catalyst from coked adsorbent is continued. Though it is not shown in Fig 2, riser 35 employed in the present invention may also be located externally. In such situation, the cyclones are connected to the riser 35 top and the diplegs of these cyclones are connected to stripper cum separator 37 at the interface of catalyst-adsorbent bed. The present invention also includes recycling of coked adsorbent 63 separated in stripper cum separator 37 directly to riser entry 32 without under going regeneration step via recycle adsorbent stand pipe 60(A) and slide valve 61 is used to control coked adsorbent flow to riser entry 32. Other wise, instead of oxygen containing gas or air, steam is used in adsorbent regenerator 54 for the purpose of keeping fluidization conditions required. This provision is very helpful when calcined petroleum coke is used as an adsorbent. Though not indicated in Fig.2 there is a provision for adding or withdrawing adsorbent and catalyst to/from catalyst regenerator 44 and adsorbent regenerator 54 Fig 3 illustrates the FCC apparatus of the present invention wherein stripper cum separator (7) is employed to perform dual functions, firstly as a conventional stripper and secondly as a separator device to separate catalyst from adsorbent using steam (6) as a stripping/fluidizing media. The superficial velocity of steam in stripper cum separator (7) is maintained in such a way that two distinctly different layers (depending upon the particle size/density of catalyst and adsorbent) i.e. a layer of catalyst and another layer of adsorbent (33 and 32) are formed in stripper cum separator (7).

Full Text

FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION: "An improved process for the preparation of Valsartan and its intermediates"
2. APPLICANT:
(a) NAME: IPCA LABORATORIES LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai - 400 067,
Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed

ORIGINAL
490/MUM/2008
GRANTED
6-7-2007

22 SEP 2005

Field of invention :
The present invention relates to an improved process for the preparation of a known pharmaceutical agent, Valsartan, and its intermediates in substantially pure enantiomeric form.
Background of the invention:
(S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine commonly known as Valsartan has the following structure (Formula I):

(I)

Valsartan is a member of the class of agents termed angiotensin-II (AT) receptor antagonists having effective anti-hypertensive activity with an excellent profile of safety and tolerability. Activation of AT receptors in the outer membrane of vascular smooth muscle cells of the heart and arteries causes the tissues to constrict. AT-I receptors are activated by an octa-peptide, angiotensin-II. Angiotensin-II helps to maintain constant blood pressure despite fluctuations in a person's state of hydration, sodium intake and other physiological variables. Angiotensin-II also performs the regulatory tasks of inhibiting excretion of sodium by the kidneys, inhibiting nor-ephedrin reuptake and stimulating aldosterone biosynthesis. By inhibiting angiotensin-II binding to AT receptors, valsartan disrupts the vasoconstriction mediated by AT receptors.
Valsartan is therefore a non-peptide angiotensin-II antagonist, inhibits the actions of angiotensin-II on its receptors, thus preventing the increase of blood pressure produced by the hormone-receptor interactions. Hence it is used in the treatment of cardiovascular

complaints such as hypertension and heart failure. Comparative trial studies have shown that valsartan is as effective as angiotensin-converting enzyme, (ACE) inhibitors, calcium-channel blockers and a-blockers, and is generally better tolerated. Valsartan is marketed as the free acid under the trade name DIOVAN, however, its combination with diuretics, such as hydrochlorothiazide have specific advantage as anti-hypertensive agent.
The synthesis of Valsartan and its intermediates of formula II, III and IV are reported in patent (US patent no. 5,399,578) and Bioorganic & Medicinal Chemistry Letters, vol. 4, pp 29-34,1994, via the following method as shown in Scheme I:

\-J \-J Scheme I Although the process appears to be practical but involves many disadvantages from the point of view of purity/yield of valsartan and its intermediates obtained by following the

method outlined in '578 patent. The major problems are incomplete reactions, contamination of valsartan with a number of impurities or starting material/intermediates and lower chiral purity of valsartan obtained.
One of the major disadvantage is the incomplete reaction of (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester or salts thereof with valeroyl chloride in chlorinated solvents in the preparation of (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester of formula III and thus results in contamination of compound II. This impurity in turn is carried forward in subsequent reaction steps and results in valsartan of low purity.
A further disadvantage of prior method is the contamination of organotin impurity in the penultimate intermediate of valsartan namely, (S)-N-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester of the formula IV (benzyl valsartan), during the tetrazole formation of formula III. An effective purification or means to remove the organotin by-product is not described or disclosed in '578 patent. As a result the catalyst (palladium -charcoal) gets poisoned in the presence of organotin impurity during the debenzylation of benzyl valsartan (IV) and necessitates a very high loading of palladium- charcoal for completing the reaction.
The prior processes employ solvents like DMF during the preparation of compound of formula II and formula III and the need of the hour is the more greener chemistry, environmental friendly solvents and conditions etc.
Yet another problem is the racemization of valsartan or its intermediates during the
reaction conditions or purification processes as described in '578 patent. Racemization
herein means the process of a relatively pure substance becoming a mixture of
enantiomeric forms. Valsartan is used in the enantiomerically pure (S)-N-[(2'-(lH-
tetrazol-5-yl)biphenyl-4-yl)methyl]-N-valeroyl-(L)-valine form in pharmaceutical
compositions.

Thus there is a need in the art for an improved and cost-effective synthetic process for the preparation of valsartan and precursors thereof in its enantiomerically pure form.
Objects of the invention:
It is an objective of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art or to provide a useful alternative.
It is an object of the present invention in its preferred form to provide an industrial process for the preparation of valsartan substantially in its pure enantiomeric form. Other objectives of this invention include establishment of suitable purification methods to remove the organo-tin by-product from benzyl valsartan, overcome the incomplete reactions during the intermediates preparation, speeding-up the reactions and providing suitable environmentally friendly solvents in the process for Valsartan.
Summary of the invention:
Accordingly, the present invention relates to an improved method for the preparation of valsartan having an enantiomeric purity of at least 99.8%
In one embodiment of the present invention, the intermediate compound of Formula II is prepared by reacting a compound of Formula (Ha) with compound of Formula (IIb) in a heterogeneous solvent system/medium, preferably in a mixture of water and an organic solvent, in presence of an inorganic base and isolating it as hydrochloride salt. The said reaction may be optionally performed in presence of a catalyst.
In another embodiment of the present invention, the compound II is acylated with valeroyl chloride in presence of an organic base in solvents selected from non-polar solvents like toluene, xylene etc. till completion of the starting compound II to at least 99.8% in a short period of time.
In yet another embodiment of the present invention benzyl valsartan substantially free of the organotin impurity is provided by a reaction of Compound III with tributyl tin azide

in toluene or xylene and purifying the isolated crude benzyl valsartan contaminated with organotin impurity from a first solvent that is a ternary solvent mixture, characterized by combination of hydrophilic organic solvent selected from C1 to C4 alcohol, non-polar organic solvent like hexane or toluene or the like and water, followed by crystallizing from a second solvent such as a non-polar organic solvent or a polar aprotic solvent or mixtures thereof.
In a further aspect, the present invention provides a process for debenzylation of benzyl valsartan substantially free of organotin impurity using palladium carbon in significantly lower catalyst loading at ambient temperature in a hydrophilic organic solvent selected from C1 to C4 alcohol followed by crystallizing valsartan of enantiomeric purity of at least 99.8 % from solvents mixture such as ethyl acetate and hexane or ethyl acetate and ether at a temperature below 60°C.
Detailed description of the invention:
The present invention thus provides a process for preparation of valsartan and its intermediates in substantially pure enantiomeric form. The details of the present process are described herein.
X is any halogen. More preferable halogen is bromine.

In the first step, the compound of the general Formula Ha is reacted with compound of general formula IIb in presence of a base and optionally in presence of a catalyst. In a preferred embodiment of the present invention the above reaction step is carried out in a heterogeneous solvent mixture comprising water and a non-polar hydrocarbon solvent. In the general formula Ha:

X is any halogen. More preferable halogen is bromine. In the general formula lib or a salt thereof:

R represents any carboxyl protecting group and however the preferred carboxyl protecting group is methyl or benzyl group. In the reaction the compound lib may be used as its acid salt preferably hydrochloric acid salt or p-toluene sulphonic acid salt and more preferably p-toluene sulphonic acid salt. If an acid salt is employed in the reaction an excess amount of base is used, which is required to neutralize the salt to free compound IIb.
The heterogeneous solvent mixture comprises a non-noxious solvent water and an organic solvent preferably a hydrocarbon solvent such as toluene, xylene. The organic solvent and water mixture comprises, based on the total volume of the solvent mixture, from about 40% to 80% of non-polar organic solvent and about 60% to 20% of water. Preferably the reaction is carried out in a mixture of non-polar hydrocarbon solvent and water comprising, based on the total volume of the solvent mixture, from about 40% to 60% of non-polar hydrocarbon solvent and about 60% to 40% of water.
As described above the preferred non-polar hydrocarbon solvents are selected from C6 -C9 aromatic hydrocarbon or C5 - C8 aliphatic hydrocarbon or C5 - C8 alicyclic hydrocarbon. Other hydrocarbons useful in the practice of the present invention will be apparent to the skilled artesian. The preferred non-polar solvent is selected from, but is not limited to, toluene, xylene, hexane, cyclohexane or mixtures thereof. The most preferred non-polar solvent is toluene.
The basic material used in the reaction is an inorganic base such as carbonate or bicarbonate salt of an alkali metal and preferably the alkali metal salt is sodium carbonate, potassium carbonate or sodium bicarbonate.

The reaction may optionally be carried out in the presence of a catalyst. Preferred catalyst is selected form potassium iodide, sodium iodide, or a phase-transfer catalyst such as tetrabutyl ammonium bromide, tetrabutyl ammonium chloride or a combination of phase-transfer catalyst and sodium/potassium iodide.
The reaction is carried out at a temperature from an ambient temp to the reflux temperature of the reaction mixture. More preferably heat is used to effect the completion of reaction at a temperature of about 40°C - 60°C and the reaction completes in a period of about 20 hours to 30 hours.
On completion of the reaction, the intermediate compound II is isolated from the reaction mixture by phase separation & water washing, and acidification of the organic layer. The reaction product (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester of formula II, gets separated out in the form of its hydrochloride salt after acidification of the reaction mixture using hydrochloric acid, gaseous hydrochloric acid or aqueous hydrochloric acid to a pH of 1-4.
The precipitated (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride shows a purity above 95% with an yield of about 85%. The (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride is used as such in subsequent reaction or may be isolated as its free base by neutralization procedure known in the art.
In a second step of the present inventi on, the hydrochloride salt of (S)-N-[(2'-
cyanobiphenyl-4-yI)methyl]-(L)-valine benzyl ester (Formula II) is reacted with a
compound of formula IIe as shown below in presence of a base like diisopropylethylamine,

v=/ (II)
or a salt thereof with a compound of formula (lie) ,0

According to the present invention the above process step, reaction of (S)-N-[(2'-cyano-biphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride with compound lie, is carried out in a non-polar hydrocarbon solvent. The preferred non-polar solvent is selected from C6 - C9 aromatic hydrocarbon or C5 - C8 aliphatic hydrocarbon or C5 - C8 alicyclic hydrocarbon and is preferably toluene.
The reaction is carried out at a temperature between 0°C to the reflux temperature and preferably between 20°C to the reflux temperature of the solvent. Most preferably the reaction is carried out between 25°C - 35°C and the reaction completes in a span of 1 to 5 hours.
In the third step, the cyano group in compound of formula III is converted into tetrazole ring system by reaction with tributyltin azide to produce the penultimate intermediate of valsartan called benzyl valsartan. Usually the tributyltin azide is added in three lots. Toluene is used as solvent and the reaction is effected at reflux temperature. In a preferred embodiment of the present invention the stage III product on water washings is directly employed in the tetrazole formation when the solvent is toluene or xylene. After the completion of tetrazole formation, the benzyl valsartan is released from the tributyl tin complex by passing dry hydrochloric acid gas to the reaction mixture, toluene is decanted off and the residue is taken in water immiscible solvent, washed with water till free of acid. The compound of formula IV is isolated as oil in crude form.

Generally the second step and third step is carried out insitu without isolating the product of second step.
The present invention provides a purification method for effective removal of the organotin impurity from benzyl valsartan of the formula (IV)

The purification process of the present invention includes a first crystallization of benzyl valsartan from a ternary solvent mixture comprises a hydrophilic organic solvent, a non-polar organic solvent and water, and a second crystallization from a polar aprotic solvent or non-polar organic solvent or mixtures thereof.
The hydrophilic organic solvents used in the ternary solvent mixture in the first purification are selected from C1 to C4 alcohols especially isopropanol. The non-polar organic solvents are selected from hydrocarbon solvents like hexane, toluene, cyclohexane or the like. The composition of the ternary mixture is as follows: the ratio of hydrophilic organic solvent to inert non-polar organic solvent is in the range of about 1:0.5 to 1:100 parts by weight and preferably is in the range of about 1:0.5 to 1:25 parts by weight and more preferably is in the range of about 1:0.5 to 1:10 parts by weight, on the basis of 1 part by weight of compound of formula IV. The ratio of water to combination of hydrophilic organic solvent and inert non-polar organic solvent is in the range of about 0.5: 1 to 10:1 parts by weight and preferably is in the range of about 0.5:1 to 5:1 parts by weight, on the basis of 1 part by weight of compound of formula IV.
In a preferred form, water is added to a pre-formed solution of compound of formula IV (Benzyl valsartan) in a mixture of hydrophilic organic solvent and non-polar organic

solvent between 0°C to reflux temperature. Preferably the addition is carried out between 25 °C - 35°C and the benzyl valsartan precipitates out of the solution. The precipitated compound of formula IV is isolated by filtration or other conventional means at ambient temperature or by further cooling to 0°C.
According to the present invention, benzyl valsartan is further purified from a second solvent, preferably the non-polar organic solvent or polar aprotic solvent or mixtures thereof, to obtain benzyl valsartan substantially free of organotin impurity in high enantiomeric purity.
The non-polar organic solvent is selected from C6 - C9 aromatic hydrocarbon, C5 - C8 aliphatic hydrocarbon or C5 - C8 alicyclic hydrocarbon. The non-polar organic solvents are selected from hydrocarbon solvents like hexane, toluene or the like and the inert polar aprotic solvent is ethyl acetate.
In the process of purification the non-polar organic solvent is added to a solution of benzyl valsartan in polar aprotic solvent between 0°C to reflux temperature. Preferably the addition of non-polar organic solvent is carried out between 25°C - 35°C to precipitate benzyl valsartan substantially free of organotin impurity.
The combination of non-polar organic solvent to ethyl acetate preferably has a ratio in which ethyl acetate to the non-polar organic solvent is in the range of about 1:0 to 1:100 parts by weight and preferably is in the range of about 1:0 to 1:50 parts by weight and more preferably is in the range of about 1:0 to 1:25 parts by weight, on the basis of 1 part by weight of compound of formula IV. The precipitated benzyl valsartan can be separated from the mixture by conventional means such as filtration and can be optionally dried at a temperature below 60°C.
The benzyl valsartan obtained above is subjected to hydrogenation in presence of palladium-charcoal to obtain valsartan. The present invention is characterized by a lower loading of costly palladium-charcoal catalyst in the debenzylation of benzyl valsartan substantially free of organotin impurity. In the presence of organotin impurity, the

catalyst gets poisoned and looses the activity and thus necessitates a heavy loading of costly palladium-charcoal catalyst in the prior art. The present invention has reduced the palladium-charcoal quantity by about 70% with respect to the prior art processes. After the completion of the reaction, the product was filtered, concentrated and solution of valsartan in an aqueous basic solution is prepared. The aqueous basic solution may be that of an alkali metal or alkaline earth metal salt such as sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide or potassium hydroxide. The aqueous layer is washed with chlorinated solvent such as methylene dichloride or ethylene dichloride. The aqueous solution is then rendered acidic using aqueous acidic solutions of inorganic acids such as hydrochloric acid, sulfuric acid or acetic acid. Precipitated valsartan is then extracted using an organic solvent such as ethyl acetate or isobutyl methyl ketone or methyl propyl ketone. The organic phase is concentrated under reduced pressure to dryness; residue is suspended / slurry washed with hydrocarbon solvent such as toluene, hexane, cyclohexane, a combination of hydrocarbon solvent with ethyl acetate or diisopropyl ether or a mixture thereof and valsartan can be separated from the mixture by decanting, filtering, centrifuging or using other similar processing methods of isolation of solids from liquids known to a person skilled in the art, or any combination of such separation methods and is optionally followed by a wash with water.
Valsartan after acidification and extraction in above said solvent can also be isolated by slurryfication, at a temperature below 60°C, from premix solvent mixtures such as ethyl acetate-hexane or ethyl acetate-diisopropylether optionally in presence of water. Valsartan can be separated from the mixture by decanting, filtering, centrifuging or using other similar processing methods of isolation of solids from liquids known to a person skilled in the art, or any combination of such separation methods and is optionally followed by a wash with water.
Isolated valsartan is dried, at a temperature below 60°C, by air drying, vacuum drying or fluidized bed drying or using other similar drying methods of solids known to a person skilled in the art, or any combination of such drying methods.

The temperature of reaction as well as isolation and drying is crucial for getting higher enantiomeric excess as at higher temperature valsartan tends to racemize. The valsartan obtained by following the process of the present invention has a purity of at least 99.7% and the R-isomer content is less than 0.10%.
This drastic yield and purity improvement caused by the above-described variations thus lead to an efficient and commercially acceptable synthetic process for the preparation of valsartan.
This higher enantiomeric purity and yield starting from compound of Formula II constitutes a considerable technical advance with respect to the process described in US 5,399,578 patent.
The invention is explained in more detail in the following working examples. The examples, which illustrate improvement in the method according to the invention, have a purely illustrative character and do not limit the extent of the invention in any respect.
Example 1
(S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride 4-bromomethyl-2'-cyanobiphenyl (15gm, 0.055 mol), L-valine benzyl ester tosylate (20.9 gm, 0.055 mol), potassium carbonate (21 gm, 0.152 mol), potassium iodide (0.21 gm) were heated to 50-55°C in toluene (63 ml) and water (63 ml) for 25 hours. After cooling down, the two phases separated out. The organic layer water washed (2 x 50 ml) and acidified with hydrochloric acid to pH 1-2, upon which the product crystallized out; 17.9 gm (75%). The product purity was about 97%.
Example 2
(S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride 4-bromomethyl-2'-cyanobiphenyl (15gm, 0.055 mol), L-valine benzyl ester tosylate (20.9 gm, 0.055 mol), potassium carbonate (21 gm, 0.152 mol), tetrabutyl ammonium bromide (0.21 gm) were heated to 50-55°C in cyclohexane (50 ml) and water (75 ml) for 25 hours. After cooling down, the two phases separated out. The organic layer water washed and

acidified with hydrochloric acid to pH 1-2, upon which the product crystallized out; 12.4 gm (72.11%). The product purity was about 96%.
Example 3
(S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride 4-bromomethyl-2'-cyanobiphenyl (15gm, 0.055 mol), L-valine benzyl ester tosylate (20.9 gm, 0.055 mol), sodium bicarbonate (21 gm, 0.152 mol), tetrabutyl ammonium bromide (0.21 gm) were heated to 50-55°C in toluene (63 ml) and water (63 ml) for 30 hours. After cooling down, the two phases separated out. The organic layer water washed and acidified with hydrochloric acid to pH 1-2, upon which the product crystallized out; 16.7 gm (70%). The product purity was about 92%.
Example 4
(S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride 4-bromomethyl-2'-cyanobiphenyl (15gm, 0.055 mol), L-valine benzyl ester tosylate (20.9 gm, 0.055 mol), potassium carbonate (21 gm, 0.152 mol), tetrabutyl ammonium bromide (0.21 gm) were heated to 50-55°C in xylene (63 ml) and water (63 ml) for 25 hours. After cooling down, the two phases separated out. The organic layer water washed and acidified with hydrochloric acid to pH 1-2, upon which the product crystallized out; 17.4 gm (73%). The product purity was about 97%.
Example 5
(S)-N-[(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine benzyl ester hydrochloride 4-bromomethyl-2'-cyanobiphenyl (15gm, 0.055 mol), L-valine benzyl ester tosylate (20.9 gm, 0.055 mol), potassium carbonate (21 gm, 0.152 mol), tetrabutyl ammonium bromide (0.21 gm) and potassium iodide (0.21 gm) were heated to 50-55°C in toluene (63 ml) and water (63 ml) for 25 hours. After cooling down, the two phases separated out. The organic layer water washed and acidified with hydrochloric acid to pH 1-2, upon which the product crystallized out; 21.6 gm (90%). The product purity was about 97%.

Example 6
(S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride 4-bromomethyl-2'-cyanobiphenyl (15gm, 0.055 mol), L-valine benzyl ester tosylate (20.9 gm, 0.055 mol), potassium carbonate (21 gm, 0.152 mol) were heated to 50-55°C in toluene (63 ml) and water (63 ml) for 25 hours. After cooling down, the two phases separated out. The organic layer water washed and acidified with hydrochloric acid to pH 1-2, upon which the product crystallized out; 17.2 gm (72%). The product purity was about 96%.
Example 7
(S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride 4-bromomethyl-2'-cyanobiphenyl (4.2 kg, 0.0154 mol), L-valine benzyl ester tosylate (5.85 kg, 0.0154 mol), potassium carbonate (5.88 kg, 0.0426 mol), potassium iodide (0.059 kg) were heated to 50-55°C in toluene (17.6 It) and water (17.6 It) for 25 hours. After cooling down, the two phases separated out. The organic layer water washed (2 x 14 It) and acidified with hydrochloric acid to pH 1-2, upon which the product crystallized out; 5.04 kg (75.4%). The product purity was about 97%.
Example 8
(S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester To sodium bicarbonate (65 gm, 0.774 mol) in water (800 ml) and toluene (400 ml) was added (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride (210 gm, 0.483 mol) at 25°C. Stirred for an hour, layers separated and the toluene layer was washed with brine solution. It was dried over sodium sulfate. To the dried toluene layer containing (S)-N-[(2'-cyano biphenyl-4-yl)methyl]-(L)-valine benzyl ester was added N,N-diisopropylethylamine (101.8 gm, 0.786 mol) at 25°C. It was cooled down to 20°C and valeroyl chloride (80 gm, 0.664 mol) was added over a period of about 30 minutes. After the completion of reaction by TLC check, 50 ml water was added and further stirred for 30 minutes. Layers were separated and to the organic layer at 0°C was added IN hydrochloric acid solution till pH was about 1-3, stirred for 30 minutes and layers separated. To the organic layer added 10% sodium bicarbonate solution till pH of

reaction mass was about 7-8. Layers separated and organic layer washed with 200 ml water and then with 200 ml brine solution. The organic layer evaporated, yielding 228 gm (98%) brownish oily substance. HPLC purity 96%.
Example 9
(S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine
To the dried toluene layer ((Solution B) as described in part b mentioned below)) was added; sodium azide (70 gm, 1.08 mol) and tibutyl tin chloride (350 gm, 1.07 mol). The reaction mass was heated to reflux. After about 20 hrs 2nd lot of sodium azide (10 gm, 0.154 mol) and tibutyl tin chloride (50 gm, 0.154 mol) was added. The reflux further continued for 20-24 hrs. After the completion of reaction by TLC check, it was cooled down to about 15°C and dry hydrochloric acid gas passed through the toluene layer till the decolorisation of toluene was observed. Toluene layer was decanted off and the residue washed with 100 ml of toluene. The residue was partitioned between methylene chloride and 10% sodium bicarbonate solution and stirred at 25-30°C for 30 minutes. Layers separated, organic layer washed with brine solution and dried over sodium sulfate. The organic layer evaporated, yielding 240 gm brownish oil. HPLC assay 91%. 23 gms of above oil was taken in 40 ml IPA and heated to get clear solution. To the reaction mass was added 200 ml hexane. It was further cooled to about 10-20°C and 250 ml water added in about 60 minutes. It was further stirred at 25-30°C for 60 minutes and filtered; 18 gm (78%). MP 106-108°C; HPLC assay 93-96%.
Solution B can be prepared as follows:
a) (S)-N-[(2'-cyano biphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride 4-bromomethyl-2'-cyanobiphenyl (15gm, 0.055 mol), L-valine benzyl ester tosylate (20.9 gm, 0.055 mol), potassium carbonate (21 gm, 0.152 mol), potassium iodide (0.21 gm) were heated to 50-55°C in toluene (63 ml) and water (63 ml) for 25 hours. After cooling down, the two phases separated out. The organic layer water washed (2 x 50 ml) and

acidified with hydrochloric acid to pH 1-2, upon which the product crystallized out; 17.9 gm (75%). The product purity was about 97%.
b) (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester. To sodium bicarbonate (65 gm, 0.774 mol) in water (800 ml) and toluene (400 ml) was added (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride (210 gm, 0.483 mol) at 25°C. Stirred for an hour. Layers separated and the toluene layer dried over sodium sulfate. To the dried toluene layer containing (S)-N-[(2'-cyano biphenyl-4-yl)methyl]-(L)-valine benzyl ester was added N,N-diisopropylethylamine (101.8 gm, 0.786 mol) at 25°C. It was cooled down to 15°C and valeryl chloride (80 gm, 0.664 mol) was added over a period of about 60 minutes. After the completion of reaction by TLC check, 100 ml water was added and further stirred for 30 minutes. Layers were separated and to the organic layer at 10°C was added IN hydrochloric acid solution till pH was about 1-3, stirred for 30 minutes and layers separated. To the organic layer added 10% sodium bicarbonate solution till pH of reaction mass was 7-8. Layers separated and organic layer washed with 200 ml water and then with 200 ml brine solution. The organic layer dried using sodium sulfate. The dried toluene layer (Solution B) was further used as such.
Example 10
(S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)-
biphenyl-4-ylmethyl] -amine
Using the toluene layer from part-a the title compound was prepared analogously to
Example 9.
5 gms of the above solid was taken in 15 ml Toluene, heated to get clear solution and
stirred at ambient temperature and filtered; 4 gms (80%). MP 115.7-115.8°C; HPLC/
assay 99.54%.
The starting material can be prepared, for example, as follows:
a) (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester

To sodium bicarbonate (65 gm, 0.774 mol) in water (800 ml) and toluene (400 ml) was added (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride (210 gm, 0.483 mol) at 25°C. Stirred for an hour. Layers separated and the toluene layer dried over sodium sulfate. To the dried toluene layer containing (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester was added N,N-diisopropylethylamine (101.8 gm, 0.786 mol) at 25°C. It was cooled down to 15°C and valeryl chloride (80 gm, 0.664 mol) was added over a period of about 60 minutes and further processed analogously to Example 9b.
Example 11 (S)-N-( 1 -benzyloxycarbonyl-2-methyl-prop-1 -yl)-N-pentanoyl-N- [2' -(1 H-tetrazol-5 -yl)-biphenyl-4-ylmethyl] -amine
Using the toluene layer from part-a the title compound was prepared analogously to Example 9.
5 gms of the above solid was taken in 10 ml ethyl acetate and heated to get clear solution. Added 20 ml hexane and cooled down to 25-30°C upon which the product crystallized out; 3.5 gm (70%). MP 115.2-115.8°C; HPLC assayl00.15%.
The starting material can be prepared, for example, as follows:
a) (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester
Starting with 210 gms of (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester
hydrochloride the title compound was prepared analogously to Example 9b.
Example 12 (S)-N-( 1 -benzyloxycarbonyl-2-methyl-prop-1-yl)-N-pentanoyl-N-[2' -(1 H-tetrazol-5 -yl)-biphenyl-4-ylmethyl]-amine
Using the toluene layer from part-a the title compound was prepared analogously to Example 9.

5 gms of the above solid was taken in 15 ml toluene and heated to get clear solution. Added 10 ml hexane and cooled down to ambient temperature upon which the product crystallized out; 4.5 gm (90%). MP 115.9-116°C, HPLC assaylOO.46%.
The starting material can be prepared, for example, as follows:
a) (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester
Starting with 210 gms of (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester
hydrochloride the title compound was prepared analogously to Example 9b.
Example 13
(S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)-
biphenyl-4-ylmethyl]-amine
Using the toluene layer from part-a the title compound was prepared analogously to
Example 9.
1 kgs of the above solid was taken in 2 It ethyl acetate and heated to get clear solution.
Added 4 It hexane and cooled down to 25-30°C upon which the product crystallized out;
3.5 kg (70%). MP 115.2-115.8°C; HPLC assayl00.15%.
The starting material can be prepared, for example, as follows:
a) (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester
Starting with 2.1 kgs of (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester
hydrochloride the title compound was prepared analogously to Example 9b.
Example 14
(S)-N-(l -Carboxy-2-methyl-prop-1 -yl)-N-pentanoyl-N-[2' -(1 H-tetrazol-5-yl)-biphenyl-4-
ylmethyl]-amine.
A solution of 50 gm (S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-pentanoyl-N-
[2'-(lH-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine in 500 ml methanol was hydrogenated
at room temperature with the addition of 2.5 gm Pd-C (5%) till the completion of

reaction. The crude valsartan was obtained by filtration and evaporation of the solvent. It was partitioned between 500 ml of 10% sodium bicarbonate solution and 200 ml MDC. The aqueous phase was separated and rendered acidic, and the title compound isolated by extraction with ethyl acetate. It was crystallized from mixture of ethyl acetate and hexane; 34 gm (82%). HPLC 99.8% and R-isomer 0.07%.
Example 15
(S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)-biphenyl-4-
ylmethyl]-amine.
A solution of 50 gm (S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-pentanoyl-N-
[2'-(lH-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine in 300 ml methanol was hydrogenated
at room temperature with the addition of 1.25 gm Pd-C (5%) and further proceeded
analogously to example 14. It was crystallized from mixture of ethyl acetate and di-
isopropyl ether; 29 gm
(70%). HPLC 99.83% and R-isomer 0.03%.
Example 16
A solution of 50 gm (S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine in 500 ml methanol was hydrogenated at room temperature with the addition of 1.25 gm Pd-C (5%) till the completion of reaction. The crude valsartan was obtained by filtration and evaporation of the solvent. The residue was partitioned between 500 ml of 10% sodium bicarbonate solution and 200 ml MDC. The aqueous phase was separated and rendered acidic, and the title compound isolated by extraction with ethyl acetate. The organic phase was distilled under reduced pressure to dryness, the residue was suspended in a mixture of ethyl acetate:hexane at ambient temperature, filtered, washed with water and dried; 34 gm (82%). HPLC 99.8% and R-isomer 0.05%.
Example 17
A solution of 50 gm (S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-pentanoyl-N-
[2'-(lH-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-amine in 500 ml methanol was hydrogenated

at room temperature with the addition of 2.5 gm Pd-C (5%) till the completion of reaction. The crude valsartan was obtained by filtration and evaporation of the solvent. It was partitioned between 500 ml of 10% sodium bicarbonate solution and 200 ml MDC. The aqueous phase was separated and rendered acidic, and the title compound was isolated by extraction with ethyl acetate, The organic phase was distilled under reduced pressure to dryness, slurried in a mixture of ethyl acetate:hexane:water (ratio 2:5:1), filtered and dried; 34 gm (82%). HPLC 99.8% and R-isomer 0.02%.
Comparative Example 1
(S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester 6.2 gm (15.5 mmol) of (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester and 8.0 ml N,N-diisopropylethylamine, dissolved in 50 ml of methylene chloride, are treated with 2.3 ml of valeryl chloride with stirring. The reaction mixture was stirred at room temperature for 20-25 hours until starting amine can no longer be detected by TLC. After evaporating in a water jet vacuum, the reaction mixture was partitioned between 82 ml water and 826 ml ethyl acetate. The organic phase was washed successively with 40 ml each of 2N hydrochloric acid, saturated NaHCO3 solution and brine, dried over magnesium sulfate and evaporated in vacuum. The title compound obtained as brown oil. HPLC purity 72%.
Comparative Example 2
(S)-N-(l-benzyloxycarbonyl-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)-biphenyl-4-ylmethyl] -amine.
6.6 gm (13.6 mmol) of (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-valine benzyl ester and 6.0 gm (18 mmol) of tributyltin azide in 75 ml of o-xylene are heated to boiling with stirring for 48 hours. After 24 hours, 2.0 gm of tributyltin azide are added. After cooling, the solution was diluted with about 125 ml of toluene, treatd with 110 ml IN potassium hydroxide solution and stirred for 20 minutes. The aqueous phase was separated and rendered acidic with IN hydrochloric acid solution, the product extracted in ethyl acetate. The title compound after evaporation of solvent was obtained as oil. HPLC assay 86-88%.

We claim,
1. A process for the preparation of valsartan of formula (I)

comprising the steps of:
i) reacting a compound of formula (Ha)

wherein X is any halogen, with a compound of formula (IIb)

or a salt thereof, wherein R represents carboxy protecting group, characterized in that the reaction is carried out in a heterogeneous solvent mixture comprising of water and non-polar hydrocarbon solvent, in presence of a basic material and optionally in presence of catalyst to obtain a compound of Formula II;

ii) acylating said compound of formula (II) or a salt thereof

with a compound of formula (IIc)

in presence of an organic base characterized in that the reaction is carried out in non-polar hydrocarbon solvent to obtain a compound of Formula HI;

(III) iii) reacting said compound (III) with tributyl tin azide in an aromatic solvent and isolating benzyl valsartan of formula IV characterized in that the benzyl valsartan is further purified from a mixture of solvents to get benzyl valsartan substantially free of organotin impurity content; and

iv) hydrogenating the benzyl valsartan substantially free of organotin content in presence of 2.5 to 5.0 % wt/wt of palladium -charcoal catalyst relative to starting benzyl valsartan to obtain valsartan.
2. The process as claimed in claim 1, wherein said heterogeneous solvent mixture of non-polar hydrocarbon solvent and water in step (i) comprising, based on the total volume of the solvent mixture, from about 40% to 60% of the non-polar hydrocarbon solvent and about 60% to 40% of water.
3. The process as claimed in claim 2, wherein the non-polar hydrocarbon solvent is toluene, xylene, hexane, cyclohexane or mixtures thereof.
4. The process as claimed in any one of the preceding claim, wherein the catalyst in step (i) is selected from potassium iodide, sodium iodide, or a phase-transfer catalyst such as tetrabutyl ammonium bromide, tetrabutyl ammonium chloride or a combination of phase-transfer catalyst and sodium/potassium iodide.
5. The process as claimed in claim 1, wherein step (iii) is carried out without isolating the compound of step (ii).
6. The process as claimed in claim 1 or 5, wherein benzyl Valsartan (IV) in step (iii) is purified first from a ternary solvent medium comprising a hydrophilic organic solvent, non-polar organic solvent and water, followed by crystallizing from a second solvent system comprising a non-polar organic solvent or a polar aprotic solvent or mixtures thereof.
7. The process as claimed in claim 6, wherein said ternary solvent mixture has hydrophilic organic solvent to non-polar organic solvent ratio in the range of about 1:0.5 to 1:100 parts, and hydrophilic organic solvent & non-polar organic solvent to

water ratio is in the range of about 1:0.5 to 1:10 parts by weight relative to benzyl Valsartan.
8. The process as claimed in claim 7, wherein the hydrophilic organic solvent is selected from C1 to C4 alcohols.
9. The process as claimed in claim 8, wherein said alcohol is IP A.
10. The process as claimed in claim 6, wherein the second purification solvent system has polar aprotic solvent to non-polar organic solvent ratio in the range of about 1:0 to 1:100 parts by weight relative to benzyl valsartan.
11. The process as claimed in claim 6 or 10, wherein the non-polar organic solvent is selected from the group of C6 - C9 aromatic hydrocarbon or C5 - C8 aliphatic hydrocarbon or C5 - C8 alicyclic hydrocarbon.
12. The process as claimed in claim 11, wherein the non-polar organic solvent is toluene, hexane or mixtures thereof.
13. The process as claimed in claim 6 or 10, wherein said polar aprotic solvent is ethyl acetate.
14. A process as herein described in accompanying text, description and examples.
Dated this 22nd day of September 2005
Dr. Gopakumar G. Nair Agent for the Applicant

devices 39A & 39B. Fine particles of spent catalyst and coked adsorbent carried along with hydrocarbon vapors to the reactor 38 are separated using cyclones 40A & 40B.The diplegs of 39A, 39B, 40A & 40B are terminated close to spent catalyst and coked adsorbent bed interface in stripper cum separator 37. As described above, spent catalyst and coked adsorbent mixture collected in stripper cum separator 37 is separated in to two layers 62 & 63 and taken to respective regenerators 44, & 54 for regeneration/reactivation. The cycle of regeneration, feed contaminants removal, cracking reaction followed by gas-catalyst-adsorbent separation and then separation of spent catalyst from coked adsorbent is continued. Though it is not shown in Fig 2, riser 35 employed in the present invention may also be located externally. In such situation, the cyclones are connected to the riser 35 top and the diplegs of these cyclones are connected to stripper cum separator 37 at the interface of catalyst-adsorbent bed.
The present invention also includes recycling of coked adsorbent 63 separated in stripper cum separator 37 directly to riser entry 32 without under going regeneration step via recycle adsorbent stand pipe 60(A) and slide valve 61 is used to control coked adsorbent flow to riser entry 32. Other wise, instead of oxygen containing gas or air, steam is used in adsorbent regenerator 54 for the purpose of keeping fluidization conditions required. This provision is very helpful when calcined petroleum coke is used as an adsorbent. Though not indicated in Fig.2 there is a provision for adding or withdrawing adsorbent and catalyst to/from catalyst regenerator 44 and adsorbent regenerator 54
Fig 3 illustrates the FCC apparatus of the present invention wherein stripper cum separator (7) is employed to perform dual functions, firstly as a conventional stripper and secondly as a separator device to separate catalyst from adsorbent using steam (6) as a stripping/fluidizing media. The superficial velocity of steam in stripper cum separator (7) is maintained in such a way that two distinctly different layers (depending upon the particle size/density of catalyst and adsorbent) i.e. a layer of catalyst and another layer of adsorbent (33 and 32) are formed in stripper cum separator (7).

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Patent Number

213571

Indian Patent Application Number

490/MUM/2005

PG Journal Number

42/2008

Publication Date

17-Oct-2008

Grant Date

08-Jan-2008

Date of Filing

19-Apr-2005

Name of Patentee

IPCA LABORATORIES LTD

Applicant Address

48, KANDIVLI INDUSTRIAL ESTATE, MUMBAI-

Inventors:

#	Inventor's Name	Inventor's Address
1	KUMAR ASHOK	A 4/203-4, STERLING CHS, SUNDERAVAN COMPLEX, ANDHERI(WEST), MUMBAI-400 053.
2	SANJAY GOVIND BARVE	73 B, CHANDRESHWAR BUILDING, J.S. ROAD, GIRGAUM, MUMBAI-400 004
3	DATTATRAY SHARMARO METIL	104-A, VIJAY VIHAR COMPLEX, RAJANIGANDHA C.H.S., EVERSHINE CITY, VASAI (EAST) TAHNE-400 208.
4	RAHUL SURESH KELKAR	A/604, BLUE GALAXY BUILDING NO. 2. GHATRAPATTI SHIVAJI RAOD, DAHISAR (EAST), MUMBAI-400 068.
5	BHARAT DINKAR SHIMPUKADE	B-A, KADADE CONRNER CHINCHAWADGAON, PUNE-411 033.
6	LAVKESH DAYASHANKAR	307, SHRI TRIMURTI APARATMENT, VINDYA-VASINI NAGAR, BUILDING NO. 5, NEAR AMARJYOTI SCHOOL, NAVGHAR RAOD, BHAYANDER (EAST), THANE-401 105.
7	MANMOHAN MADHAVRAONIMBALKAR	46, SAYANI ROAD, KHEDGULLI, PRABHADEVI, MUMBAI-400 025.
8	BHARAT DINKAR SHIMPUKADE	B-1/8, KADADE CORNER CHINCHWADGAON, PUNE-411 033.

PCT International Classification Number

C07D 257/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA