Title of Invention	"PROCESS FOR PREPARING RANOLAZINE"
Abstract	The present invention provides a cost effective and industrially advantageous process for the preparation of ranolazine of formula I, Formula I by reacting 2,6-dimethylaniline derivative with chloroacetyl chloride in the presence of base in water optionally with water miscible solvent and resulting amide intermediate is reacted with piperazine in the presence of a suitable base and the resulting piperazine derivative is further condensed with an appropriate oxirane derivative (prepared by the reaction of 2-methoxyphenol with epichlorohydrin in the presence of a base using phase transfer catalyst in water) to prepare ranoalzine.

Title of Invention

"PROCESS FOR PREPARING RANOLAZINE"

Abstract

The present invention provides a cost effective and industrially advantageous process for the preparation of ranolazine of formula I, Formula I by reacting 2,6-dimethylaniline derivative with chloroacetyl chloride in the presence of base in water optionally with water miscible solvent and resulting amide intermediate is reacted with piperazine in the presence of a suitable base and the resulting piperazine derivative is further condensed with an appropriate oxirane derivative (prepared by the reaction of 2-methoxyphenol with epichlorohydrin in the presence of a base using phase transfer catalyst in water) to prepare ranoalzine.

Full Text	FIELD OF INVENTION The present invention provides an industrial advantageous process for the preparing ranolazine, of formula I, (Formula Removed) Formula I which is an important antianginal and anti-ischemic agent. BACKGROUND OF THE INVENTION Ranolazine, of formula I, is an important antianginal and anti-ischemic agent and is chemically known as l-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine. (Formula Removed) Formula I Ranolazine has been shown to exert its anti-anginal and anti-ischemic effects without reducing heart rate or blood pressure. Ranolazine was first disclosed in U.S. patent 4,567,264. The patent described two processes for the preparation of ranolazine. The difference between the two processes resides in the fact that the substituent groups on the two nitrogen atom of the piperazine ring are introduced in different sequences. One of the two processes disclosed in above patent comprises the steps of reacting 2,6-dimethylaniline derivative with chloroacetyl chloride in the presence of triethylamine and methylene chloride to form an amide intermediate, which is reacted with 3-5 molar excess of piperazine and the resulting piperazine derivative is harvested with aqueous ammonia and further condensed with an appropriate oxirane derivative (prepared by the reaction of 2-methoxyphenol with excess of epichlorohydrin in the presence of strong base in water and dioxane) in a mixture of two solvents, methanol and toluene and ranolazine is isolated as oil using chromatographic technique and converted to dihydrochloride acid salt using excess of hydrochloric acid. The major drawbacks of above process are low yield and low purity. Further the yield and purity of oxirane derivative has not been mentioned and on repetition of exemplified experiment we have found that reaction results in large number of impurities. Removal of this impurity requires time consuming purification steps which make the process expensive and unsuitable for commercial point of view. Besides this, the patent teaches the use of dioxane solvent at this stage that is a probable carcinogen, toxic, irritant and harmful by inhalation, ingestion and through skin contact. A further drawback is the necessity of using piperazine in excess molar ratio in order to avoid the side-reaction on the other nitrogen atom of the ring during the condensation of amide intermediate with piperazine. This reaction results in the formation of hydrochloric acid as by-product, therefore 3-5 molar excess of piperazine is used that acts as a reactant as well as a base to neutralize the acid so formed. Piperazine is a costly reagent and hence its use in high molar quantity is not advisable on industrial scale. During condensation of piperazine derivative with oxirane derivative, mixture of solvents is used and further ranolazine is isolated using column chromatographic technique. Column chromatography is a cumbersome, tedious, expensive, and inconvenient unit operation and cannot be advantageously used for industrial large-scale production. PCT Publication WO 2008/047388 discloses an improved process for the preparation of ranolazine by overcoming few drawbacks of prior art process. The process comprises reacting 2-methoxyphenol with epichlorohydrin using phase transfer catalyst in the presence of organic solvent to afford oxirane derivative and condensing the same with piperazine derivative (prepared by reacting 2,6-dimethylaniline with chloroacetyl chloride in presence of base in water and water miscible solvent and the resulting chloro acetamide derivative is condensed with excess of piperazine) in the presence of organic solvent to afford ranolazine. The above process also uses large excess of piperazine which is a costly reagent. Also, the patent application discloses the use of organic solvents at different steps during the reaction. Use of large excess of organic solvents, however, raises two main problems. First it adds to the cost of the product. Second, environmental concern mitigates against the use of organic solvents and requires such use be minimized. So, in the light of the above description, it is clear that the prior art processes for the preparation of ranolazine involves the use of large excess of expensive reagents which is not advisable for large-scale production. Further, the removal of large amount of unwanted impurities formed during the reaction requires multiple purifications and results in low yields. There still exists a need for a process for the preparation of ranolazine, which may be cost effective and easily scaled up for commercial production. OBJECT OF THE INVENTION The main object of the present invention is to provide a simple and cost effective process to prepare ranolazine which is easy to implement on industrial scale. Another object of the present invention provides an efficient and industry viable process for preparing ranolazine in high yield and high purity, avoiding the use of large excess of expensive reagent like piperazine. SUMMARY OF THE INVENTION One embodiment of the present invention provides a cost effective and industrially advantageous process for the preparation of ranolazine of formula-I. (Formula Removed) Formula I More particularly, the present invention describes an improved process for the preparation of l-[3-(2-methoxyphenoxy)-2-hydroxy propyl]-4-[(2,6-dimethylphenyl) aminocarbonylmethyljpiperazine of formula I in high yield and purity, which comprises: a. reacting 2-methoxyphenol with epichlorohydrin in the presence of a base in water without using organic solvent and optionally a phase transfer catalyst to afford l-methoxy-2-(oxiranyl methoxy)benzene of formula II, (Formula Removed) Formula II b. reacting 2,6-dimethylaniline with chloroacetyl chloride in the presence of base in water, optionally in the presence of water miscible solvent to afford 2-chloro-N-(2,6-dimethylphenyl)acetamide of formula III, (Formula Removed) Formula III c. reacting 2-chloro-N-(2,6-dimethylphenyl)acetamide with piperazine in the presence of a suitable base in a suitable solvent to form iV-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV, (Formula Removed) Formula IV d. condensing iV-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV with l-methoxy-2-(oxiranyl methoxy)benzene of formula II in suitable solvent to form ranolazine. In one another embodiment, the present invention provides a process for the preparation of l-methoxy-2-(oxiranyl methoxy) benzene of formula II Formula II which comprises reacting 2-methoxy phenol with epichlorohydrin in the presence of a base in water without using organic solvent and optionally in the presence of a phase transfer catalyst. In yet another embodiment, the present invention provides a process for the preparation of highly pure iV-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV, (Formula Removed) Formula IV which comprises reacting 2-chloro-N-(2,6-dimethylphenyl)acetamide with piperazine in the presence of a suitable base in a suitable solvent. In further embodiment, the present invention provides highly pure N-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV having XRD pattern similar as given in Fig 1 and DSC as given in Fig.4. In yet another embodiment, the present invention provides a process for the preparation of ranolazine in high yield and purity from highly pure N-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV having XRD pattern similar as given in Fig 1 and DSC as given in Fig.4. BRIEF DESCRIPTION OF THE DRAWINGS Fig 1: X-ray powder diffraction pattern of N-(2,6-dimethyl phenyl)-1-piperazine acetamide Fig 2: X-ray powder diffraction pattern of N-(2,6-dimethyl phenyl)-1-piperazine acetamide hydrochloride Fig 3: X-ray powder diffraction pattern of mixture of N-(2,6-dimethyl phenyl)-1-piperazine acetamide and N-(2,6-dimethyl phenyl)-1-piperazine acetamide hydrochloride Fig 4: DSC of N-(2,6-dimethyl phenyl)-1-piperazine acetamide Fig 5: DSC of N-(2,6-dimethyl phenyl)-1-piperazine acetamide hydrochloride DETAILED DESCRIPTION OF THE INVENTION The present invention provides a cost effective and industrially advantageous process for the preparation of ranolazine of formula I in high yield and high purity, (Formula Removed) Formula I by condensing l-methoxy-2-(oxiranylmethoxy)benzene of formula II and N-(2,6- dimethyl phenyl)-1-piperazine acetamide of formula IV in the presence of suitable solvent. One embodiment of the present invention provides an improved and efficient process for preparing l-methoxy-2-(oxiranylmethoxy)benzene of formula II, an important intermediate for the preparation of ranolazine. (Formula Removed) Formula II Generally, the reaction of 2-methoxyphenol with epichlorohydrin is carried out in the presence of a base in water and optionally in the presence of a phase transfer catalyst. Typically, the process involves reacting 2-methoxyphenol with epichlorohydrin and at least one base in water without adding any solvent and optionally in the presence of a phase transfer catalyst, it is only until the work up phase, i.e. after the reaction has taken place, the solvents are added to the reaction mixture. Generally, the reaction mixture is stirred for few minutes to few hours at 20-100 °C. Preferably, the reaction mixture is stirred for 4 to 6 hours at 25-35 °C. The reaction completion is monitored by thin layer chromatography/high performance liquid chromatography. After completion of reaction, layers are separated and the aqueous layer is extracted with suitable solvent such as toluene. The combined organic layer is optionally charcoalized and distilled under vacuum to afford 1-methoxy-2-(oxiranylmethoxy)benzene free from other corresponding isomeric impurities, which can be used as such in next step. (Formula Removed) Typically, bases include, but are not limited to alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide and the like. Preferably, the base is sodium hydroxide. The phase transfer catalyst may be present in an amount of about 0.05 to about 1.0 mol, preferably 0.05 to 0.5 mol equivalents to 2-methoxyphenol, and is most preferably present in an amount of about 0.05 to about 0.18 mol equivalents to 2-methoxyphenol. Several classes of compounds are known to be capable of acting as phase transfer catalysts, such as quaternary ammonium compounds viz: benzyl trimethylammonium chloride and bromide, phosphonium compounds or synthetic resins. Phase transfer catalysts include, but are not limited to, tetrabutylammonium bromide or chloride; benzyltriethylammonium chloride; tetrabutylammonium hydroxide; tricaprylylmethylammonium chloride, dodecyl sulfate, sodium salt, such as sodium lauryl sulfate; tetrabutylammonium hydrogensulfate; hexadecyltributylphosphonium bromide; hexadecyltrimethyl ammonium bromide or resin amberlite IRA-410. Preferably, the phase transfer catalysts used in the method of the present invention include at least one of the benzyltriethylammonium chloride or resin amberlite IRA-410. Optionally, crude l-methoxy-2-(oxiranyl methoxy)benzene may be purified using high vacuum distillation at 130-150 °C at 4-5 bar pressure to afford highly pure 1-methoxy-2-(oxiranylmethoxy)benzene. Yet another key intermediate, 2-chloro-N-(2,6-dimethylphenyl) acetamide of formula III, (Formula Removed) Formula III can be prepared by the processes reported in prior art such as US patent 4,567,264, PCT publication WO 2008/047388 or as exemplified herein for reference. Typically, the process comprises reacting 2,6-dimethylaniline with chloroacetyl chloride in the presence of a base in a suitable solvent. Particularly, 2,6-dimethylaniline is reacted with chloroacetyl chloride in the presence of a base in water, water miscible solvent and mixtures thereof. Preferred water miscible solvents are selected from tetrahydrofuran, acetonitrile, dimethylformamide, methanol, ethanol, isopropanol, acetone and the like. Typically, inorganic bases include, but are not limited to alkali metal hydroxides, carbonates and bicarbonates. The alkali metal hydroxides, carbonates, and bicarbonates may include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate; preferably the base is sodium bicarbonate. The reaction is performed at a temperature of below 10 °C and it takes about 2 to 5 hours for completion of reaction. Another embodiment of the present invention provides an improved process for the preparation of N-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV (Formula Removed) Formula IV by condensing 2-chloro-iV-(2,6-dimethylphenyl)acetamide of formula III with piperazine in the presence of a suitable base in a suitable solvent. Particularly, the piperazine may be present in an amount of about 1.1 to about 3.5 mol, preferably 2.2 to 3.5 mol equivalents to 2-chloro-N-(2,6-dimethylphenyl)acetamide. Piperazine can be present in hydrous or anhydrous form. The reaction results in the formation of hydrochloric acid as a by-product during this condensation reaction. It is advantageous to use a suitable base in place of excess amount of piperazine to neutralize the hydrochloric acid. Further, it is observed that excess piperazine if not completely removed may react with compound of formula II to form following impurities of formula V and formula VI. Formula V (Formula Removed) Formula VI The removal of these impurities is difficult and may require additional purification steps, therefore use of limited amount of piperazine is beneficial. Typically, the compound of formula III is condensed with piperazine in the presence of a base in a suitable solvent. Base can be selected from inorganic bases or organic bases. Inorganic base include, but not limited to ammonia, alkali metal hydroxides, carbonates and bicarbonates such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate. Organic base include but not limited to a group of general formula NHR1R2 or NR1R2R3, wherein Ri, R2 and R3 are independently selected from a (Ci-C6)-alkyl; a cycloalkyl-(Ci-C3); a phenyl which is unsubstituted or monosubstituted or polysubstituted; a naphthyl; an anthracenyl; a saturated 5- to 8-membered heterocyclic radical which is unsubstituted or substituted by a (C\| -C3)- alkyl with the proviso thet the hetero cyclic radical is not piperazine. Preferably the organic base is selected from N,N-diisopropylethyl amine, triethylamine, pyridine and the like. Solvents include, but not limited to alcohols such as ethanol, methanol, isopropanol, isoamyl alcohol; hydrocarbons such as toluene; nitrile like acetonitrile; ether such as tetrahydrofuran; ketones such as methylisobutyl ketone, acetone; water, dimethylforrnamide, dimethylsulfoxide, dioxane and the like or mixture thereof. The reaction is conducted at 20-80 °C and it takes upto 20 hours for completion of reaction. Preferably, the reaction is conducted at 40-80 °C and it takes 1-3 hours for completion of reaction. The progress of reaction is the monitored by thin layer chromatography/high performance liquid chromatography. After completion of reaction, the reaction mass is cooled to ambient temperature, diluted with water and filtered. The filtrate is extracted with halogenated solvents such as dichloromethane or chloroform or dichloroethane. The organic layer obtained is washed with water and the solvent may be optionally removed using techniques commonly known to one skilled in the art or proceeded for the next step as such without isolating the formula IV. The solvent is preferably removed by distillation from the reaction mixture under vacuum or atmospheric pressure to obtain pureN-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV in high yield. We have observed that compound of formula IV forms its hydrochloride salt in the presence of methylene chloride during distillation step. Once hydrochloride salt formation occurs, it is difficult to hydrolyse it to free amine. Further, it is found that presence of hydrochloride salt of compound of formula IV, during the condensation of compound of formula II and compound of formula IV results in the formation of lot of impurities. Besides this, hydrochloride salt of compound of formula IV does not react with compound of formula II, thus needs purification for the removal and hence results in low yield and increases the cost of the product, it is therefore essential to suppress the formation of hydrochloride salt formation. In literature also it is reported that methylene chloride forms quaternary ammonium salts with amines at ambient temperature. It is advantageous to add another organic solvent in methylene chloride to minimize the formation of hydrochloride salt. Organic solvent include, but not limited to alcoholic solvent, DMSO. Although chloroform is a class I solvent and is not a solvent of choice due to its carcinogenicity, but compound of formula does not form its hydrochloride salt in chloroform, therefore chloroform may also be used as solvent of choice during this work up. The compound of formula IV is isolated in pure crystalline form and is having XRD as shown in Fig. 1 and DSC as shown in Fig. 4. We have isolated the pure hydrochloride salt of formula IV which is formed during the workup and is having XRD as shown in Fig. 2 and DSC as shown in Fig. 5. Alternatively, the formation of salt can be suppressed by the presence of any base viz. alkali metal carbonate or bicarbonate otherwise the yield of ranolazine will be less due to the formation of more impurities which needs purification. The present invention is advantageous as it teaches the process for the preparation of 1 -methoxy-2-(oxiranylmethoxy)benzene of formula II, in the presence of water without using any organic solvent. Thus process is avoiding use of organic solvents and hence process is cost effective and environment friendly. Further, the use of an inexpensive base instead of adding an excess of piperazine makes the process appealing from cost point of view. Yet another embodiment of the present invention provides a process for the preparation of ranolazine of formula I by the condensation of l-methoxy-2-(oxiranyl methoxy) benzene of formula II and N-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV in a suitable solvent. Suitable solvent includes, but not limited to water, halogenated solvents, alcohols, nitriles, esters, ethers, ketones, hydrocarbons or mixture thereof. Preferably, l-methoxy-2-(oxiranyl methoxy) benzene of formula II and N-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV in a suitable solvent are stirred at ambient temperature. Suitable solvent is selected from water, halogenated solvents, alcohols nitriles, esters, ethers, ketones, hydrocarbon or mixture thereof. Thereafter, the reaction mass is refluxed preferably till reaction completion. The progress of reaction is monitored by thin layer chromatography/high performance liquid chromatography. After completion of reaction, the reaction mixture is cooled to ambient temperature followed by further cooling to a temperature of below 15 °C to form ranolazine which can be isolated by methods well known in art preferably by filtration. If required, ranolazine so formed can further be purified by washing with suitable solvent or by recrystallization with suitable solvent such as alcohols or aromatic hydrocarbons to obtain highly pure ranolazine having purity greater than 99% area by HPLC in high yield. Further ralolazine can be purified by converting it to an acid addition salt of ranolazine and further hydrolyzing the acid addition salt to ranolazine. The acid used for the preparation of acid addition salt include but not limited to hydrochloric, hydrobromic, sulfuric, phosphoric, oxalic, citric, tartaric, succinic, fumaric, maleic, acetic and similar acids. The order and manner of combining the reactants at any stage of the invention are not important and may be varied. The reactants may be added to the reaction mixture as solids, or may be dissolved individually and combined as solutions. Further any of the reactants may be dissolved together as sub-groups, and those solutions may be combined in any order. The present invention will now be illustrated by the following examples, which are not intended to limit the effective scope of the claims. Consequently, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as claimed. The present invention has been described in terms of its specific embodiments and various modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of present invention. EXAMPLES Example 1 Step 1: Preparation of l-methoxv-2-(oxiranvlmethoxv)benzene Process-A To a solution of sodium hydroxide (40g, l.Omol) in demineralized water (800 ml), 2-methoxyphenol (lOOg, 0.80mol) and benzyltriethylammonium chloride (30g, 0.13mol) were added at 25-30 °C and stirred for 30 minutes. Epichlorohydrin (lOOg, 1.08mol) was added slowly to the above reaction mixture at 25-30 °C. The reaction mass was then allowed to stir for 5 hours at 25-30 °C. After completion of reaction (monitored by thin layer chromatography), the reaction mass was extracted twice with toluene and the combined organic layer was washed with water. The^ solvent was distilled under vacuum to give the product as oil which was purified by high vacuum distillation to give 103g (Yield = 71.0%) of the title compound having purity 96.44% by high performance liquid chromatography. Process-B To a solution of sodium hydroxide (4g, 0.1 mol) in demineralized water (40ml) and 2-methoxyphenol (lOg, 0.08mol), epichlorohydrin (lOg, O.llmol) and resin Amberlite IRA-410 (6.4g, 10% of total weight) were added at 25-30 °C and the reaction mass was allowed to stir for 5 hours at the same temperature. After completion of reaction (monitored by thin layer chromatography), the reaction mass was extracted twice with toluene and the combined organic layer was washed with water. The solvent was distilled under vacuum to give the product as oil which was purified by high vacuum distillation to give 8.4g of title compound. Step 2: Preparation of 2-chloro-7V-(2,6-dimethvlphenyl)acetamide To a solution of sodium bicarbonate (120g) in 1000ml of demineralized water, tetrahydrofuran (120ml), 2,6-dimethylaniline (lOOg, 0.82mol) and chloroacetyl chloride (106g, 0.94mol) were added at 0 to 5 °C. The reaction mass was then stirred for 3 hours at 0 to 5 °C. After completion of reaction (monitored by thin layer chromatography), the reaction mass was filtered, washed with demineralized water (500ml) and hexane (200ml) to give 151g (Yield = 92.6%) of the title compound as an off white solid having purity 99.74% by high performance liquid chromatography. Step 3: Preparation of N(2,6-dimethyl phenvD-1-piperazine acetamide Process-A A stirred mixture of 2-chloro-N-(2,6-dimethylphenyl)acetamide (25g, 0.13mol), piperazine (25g, 0.29mol) and potassium carbonate (25g, 0.18mol) in ethanol (75ml) was refluxed for 1 hour at 78-80 °C. After completion of reaction (monitored by thin layer chromatography), the reaction mass was diluted with demineralized water (200ml), cooled and filtered. The total filtrate was extracted with dichloromethane. The combined organic layer was washed with demineralized water and solvent was distilled completely to give 27.2g (Yield = 86.4%) of title compound having purity 98.2% by high performance liquid chromatography. Process-B A mixture of 2-chloro-N-(2,6-dimethylphenyl)acetamide (25g, 0.13mol) and piperazine (36g, 0.42mol) in ethanol (75ml) was refluxed for 3 hours at 78-80 °C. After completion of reaction (monitored by thin layer chromatography), the reaction mass was diluted with demineralized water (200ml) and reaction mass was cooled to 10 °C and filtered. The pH of the filtrate was adjusted to 11.0 with aq. ammonia solution and extracted with dichloromethane. The combined organic layer was again washed with 10% aqueous ammonia solution, demineralized water and distilled to give 28g (Yield = 89.6%) of title compound having purity 97.11% by high performance liquid chromatography. Process-C A mixture of 2-chloro-N-(2,6-dimethylphenyl)acetamide (lOg, 0.05mol) and piperazine hexahydrate (40g, 0.20mol) in ethanol (30ml) was refluxed for 3 hours. After completion of reaction (monitored by thin layer chromatography), the reaction mass was diluted with demineralized water (80ml) and the reaction mass was cooled to 5-10 °C and filtered through hyflo bed, and the filtrate was extracted with dichloromethane. The combined organic layer was washed with 5% aqueous sodium hydroxide solution, demineralized water and distilled to give 10.5g (Yield = 84%) of title compound having purity 98.32% by high performance liquid chromatography. Step 4: Preparation of Ranolazine Process-A A stirred mixture of 2-chloro-N-(2,6-dimethylphenyl)acetamide (25g, 0.13mol), piperazine (25g, 0.29mol) and potassium carbonate (25g, 0.18mol) in ethanol (75ml) was refluxed for 1 hour at 78-80 °C. After completion of reaction (monitored by thin layer chromatography), the reaction mass was diluted with demineralized water (200ml), cooled and filtered. The total filtrate was extracted with dichloromethane. The combined organic layer was washed with demineralized water and solvent was distilled completely to give 27.2g solid which was taken in ethanol (175ml), l-methoxy-2-(oxiranylmethoxy)benzene (20g, O.llmol) was added at 25 to 30 °C to the reaction mass and the reaction mass was refluxed for 3 hours. After completion of reaction (monitored by thin layer chromatography), the reaction mass was charcoalised. The filtrate was cooled to 5 to 10 °C, stirred for 3 hours at the same temperature. The crystallized product was filtered, washed with chilled ethanol (25ml) and dried to give 38g of title compound as a white solid having purity 99.54% by high performance liquid chromatography. Process-B 7V-(2,6-dimethylphenyl)-l-piperazine acetamide (lOg, 0.04mol), water (50ml) and l-methoxy-2-(oxiranylmethoxy)benzene (8g, 0.04mol) were refluxed for 3 hours. After completion of reaction (monitored by thin layer chromatography), the reaction mass was cooled to 25-30 °C and stirred for 3 hours. The precipitated product was filtered, washed with water and recrystallized from ethanol to give 1 Og of the title compound as white solid. Process-C A stirred mixture of 2-chloroN-(2,6-dimethylphenyl)acetamide (50g, 0.26mol), piperazine (50g, 0.58mol) and potassium carbonate (50g, 0.36mol) in ethanol (150ml) was refluxed for 1 hour at 78-80 °C. After completion of reaction (monitored by thin layer chromatography), the reaction mass was diluted with demineralized water (400ml), cooled and filtered. The total filtrate was extracted with chloroform. The combined organic layer was washed with demineralized water and solvent was distilled completely to give 56g solid which was taken in ethanol (350ml), l-methoxy-2-(oxiranylmethoxy)benzene (40g, 0.22mol) was added at 25 to 30 °C to the reaction mass and the reaction mass was refluxed for 3 hours. After completion of reaction, the reaction mass was charcoalised. The filtrate was cooled to 5 to 10 °C, stirred for 3 hours at the same temperature. The crystallized product was filtered, washed with chilled ethanol (50ml) and dried to give 70.5g of title compound having purity 99.33% by HPLC Process-D A stirred mixture of 2-chloro-Ar-(2,6-dimethylphenyl)acetamide (25g, 0.13mol), piperazine (25g, 0.29mol) and potassium carbonate (25g, 0.18mol) in ethanol (75ml) was refluxed for 1 hour at 78-80 °C. After completion of reaction (monitored by thin layer chromatography), the reaction mass was diluted with demineralized water (200ml), cooled and filtered. The total filtrate was extracted with dichloromethane. The combined organic layer was washed with demineralized water and organic layer was diluted with ethanol (200ml), 1-methoxy-2-(oxiranylmethoxy)benzene (20g, 0.1 lmol) was added at 25 to 30 °C to the reaction mass and the reaction mass was stirred at 60-65 °C for 3 hours. After completion of reaction, the reaction distilled to give a residue which was diluted with ethanol (175ml) and charcoalised. The filtrate was cooled to 5 to 10 "C, stirred for 3 hours at the same temperature. The crystallized product was filtered, washed with chilled ethanol (25ml) and dried to give 37g of title compound as a white solid having purity 99.04% by HPLC. WE CLAIM 1. A process for the preparation of l-[3-(2-methoxyphenoxy)-2-hydroxy propyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine (Ranolazine) of formula I, (Formula Removed) Formula I comprises the steps of: a. reacting 2-methoxyphenol with epichlorohydrin in the presence of a base in a suitable solvent preferably water without using organic solvent and optionally a phase transfer catalyst to afford 1 -methoxy-2-(oxiranyl methoxy)benzene of formula II, (Formula Removed) Formula II b. reacting 2,6-dimethylaniline with chloroacetyl chloride in the presence of base in water, optionally in the presence of water miscible solvent to afford 2-chloro-N-(2,6-dimethylphenyl)acetamide of formula III, (Formula Removed) c. reacting 2-chloro-N(2,6-dimethylphenyl)acetamide with piperazine in the presence of a suitable base in a suitable solvent to form N-(2,6-dimethyl phenyl)-!-piperazine acetamide of formula IV, and (Formula Removed) Formula IV d. condensing N-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV with l-methoxy-2-(oxiranyl methoxy)benzene of formula II in suitable solvent to form ranolazine. 2. The process according to claim 1, wherein in step a, base is alkali metal hydroxide and phase transfer catalyst is benzyltriethylammonium chloride, resin amberlite IRA-410 and the like. 3. The process according to claim 1, wherein in step b, base is alkali metal carbonate or bicarbonate or alkali metal hydroxides and water miscible solvent is selected from tetrahydrofuran, acetonitrile, dimethylformamide, methanol, ethanol, isopropanol, acetone and the like or mixture thereof. 4. The process according to claim 1, wherein in step c, wherein base is selected from inorganic base and organic base; a suitable solvent includes alcohols such as ethanol, methanol, isopropanol, isoamyl alcohol; hydrocarbons such as toluene; nitrile such as acetonitrile; ether such as tetrahydrofuran, methyl tertiary butyl ether, isopropyl ether; ketones such as methylisobutyl ketone, acetone; water, dimethylformamide, dimethylsulfoxide, 1,4-dioxane and the like or mixture thereof. 5. The process according to claim 1, wherein in step d, suitable solvent is selected from water, halogenated solvents, alcohols, nitriles, esters, ethers, ketones, hydrocarbons and mixture thereof. 6. A process for the preparation of l-methoxy-2-(oxiranyl methoxy) benzene of formula II, (Formula Removed) Formula II which comprises: reacting 2-methoxyphenol with epichlorohydrin in the presence of a base in water without using organic solvent and optionally a phase transfer catalyst. 7. The process according to claim 6, wherein base includes alkali metal hydroxide and the phase transfer catalyst includes quaternary ammonium compounds and phosphonium compounds; preferably benzyltriethylammonium chloride, resin amberliteIRA-410. 8. A process for the preparation of of N-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV, (Formula Removed) Formula IV which comprises: reacting 2-chloro-JV-(2,6-dimethylphenyl)acetamide with piperazine in the presence of a suitable base in a suitable solvent. 9. The process according to claim 8, wherein a suitable base include an inorganic base or an organic base. 10. A process for the preparation of l-[3-(2-methoxyphenoxy)-2-hydroxy propyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine (Ranolazine) of formula I, (Formula Removed) Formula I comprises condensing pure N-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV having XRD as shown in Fig 1 and DSC as shown in Fig 4, with l-methoxy-2-(oxiranyl methoxy)benzene of formula II in a suitable solvent to form ranolazine.

Full Text

FIELD OF INVENTION
The present invention provides an industrial advantageous process for the preparing ranolazine, of formula I,
(Formula Removed)
Formula I
which is an important antianginal and anti-ischemic agent.
BACKGROUND OF THE INVENTION
Ranolazine, of formula I, is an important antianginal and anti-ischemic agent and is chemically known as l-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine.
(Formula Removed)
Formula I
Ranolazine has been shown to exert its anti-anginal and anti-ischemic effects without reducing heart rate or blood pressure.
Ranolazine was first disclosed in U.S. patent 4,567,264. The patent described two processes for the preparation of ranolazine. The difference between the two processes resides in the fact that the substituent groups on the two nitrogen atom of the piperazine ring are introduced in different sequences.
One of the two processes disclosed in above patent comprises the steps of reacting 2,6-dimethylaniline derivative with chloroacetyl chloride in the presence of triethylamine and methylene chloride to form an amide intermediate, which is reacted with 3-5 molar excess of piperazine and the resulting piperazine derivative is harvested with aqueous ammonia and further condensed with an appropriate oxirane derivative (prepared by the reaction of 2-methoxyphenol with excess of epichlorohydrin in the presence of strong base in water and dioxane) in a mixture of two solvents, methanol and toluene and ranolazine is isolated as oil using chromatographic technique and converted to dihydrochloride acid salt using excess of hydrochloric acid.
The major drawbacks of above process are low yield and low purity. Further the yield and purity of oxirane derivative has not been mentioned and on repetition of exemplified experiment we have found that reaction results in large number of impurities.
Removal of this impurity requires time consuming purification steps which make the process expensive and unsuitable for commercial point of view. Besides this, the patent teaches the use of dioxane solvent at this stage that is a probable carcinogen, toxic, irritant and harmful by inhalation, ingestion and through skin contact.
A further drawback is the necessity of using piperazine in excess molar ratio in order to avoid the side-reaction on the other nitrogen atom of the ring during the condensation of amide intermediate with piperazine. This reaction results in the formation of hydrochloric acid as by-product, therefore 3-5 molar excess of piperazine is used that acts as a reactant as well as a base to neutralize the acid so formed. Piperazine is a costly reagent and hence its use in high molar quantity is not advisable on industrial scale.
During condensation of piperazine derivative with oxirane derivative, mixture of solvents is used and further ranolazine is isolated using column chromatographic
technique. Column chromatography is a cumbersome, tedious, expensive, and inconvenient unit operation and cannot be advantageously used for industrial large-scale production.
PCT Publication WO 2008/047388 discloses an improved process for the preparation of ranolazine by overcoming few drawbacks of prior art process. The process comprises reacting 2-methoxyphenol with epichlorohydrin using phase transfer catalyst in the presence of organic solvent to afford oxirane derivative and condensing the same with piperazine derivative (prepared by reacting 2,6-dimethylaniline with chloroacetyl chloride in presence of base in water and water miscible solvent and the resulting chloro acetamide derivative is condensed with excess of piperazine) in the presence of organic solvent to afford ranolazine.
The above process also uses large excess of piperazine which is a costly reagent. Also, the patent application discloses the use of organic solvents at different steps during the reaction. Use of large excess of organic solvents, however, raises two main problems. First it adds to the cost of the product. Second, environmental concern mitigates against the use of organic solvents and requires such use be minimized.
So, in the light of the above description, it is clear that the prior art processes for the preparation of ranolazine involves the use of large excess of expensive reagents which is not advisable for large-scale production. Further, the removal of large amount of unwanted impurities formed during the reaction requires multiple purifications and results in low yields. There still exists a need for a process for the preparation of ranolazine, which may be cost effective and easily scaled up for commercial production.
OBJECT OF THE INVENTION
The main object of the present invention is to provide a simple and cost effective process to prepare ranolazine which is easy to implement on industrial scale.
Another object of the present invention provides an efficient and industry viable process for preparing ranolazine in high yield and high purity, avoiding the use of large excess of expensive reagent like piperazine.
SUMMARY OF THE INVENTION
One embodiment of the present invention provides a cost effective and industrially advantageous process for the preparation of ranolazine of formula-I.
(Formula Removed)
Formula I
More particularly, the present invention describes an improved process for the preparation of l-[3-(2-methoxyphenoxy)-2-hydroxy propyl]-4-[(2,6-dimethylphenyl) aminocarbonylmethyljpiperazine of formula I in high yield and purity,
which comprises:
a. reacting 2-methoxyphenol with epichlorohydrin in the presence of a base in water without using organic solvent and optionally a phase transfer catalyst to afford l-methoxy-2-(oxiranyl methoxy)benzene of formula II,
(Formula Removed)
Formula II
b. reacting 2,6-dimethylaniline with chloroacetyl chloride in the presence of base in water, optionally in the presence of water miscible solvent to afford 2-chloro-N-(2,6-dimethylphenyl)acetamide of formula III,

(Formula Removed)
Formula III
c. reacting 2-chloro-N-(2,6-dimethylphenyl)acetamide with piperazine in the presence of a suitable base in a suitable solvent to form iV-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV,

(Formula Removed)

Formula IV
d. condensing iV-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV with l-methoxy-2-(oxiranyl methoxy)benzene of formula II in suitable solvent to form ranolazine.
In one another embodiment, the present invention provides a process for the preparation of l-methoxy-2-(oxiranyl methoxy) benzene of formula II
Formula II

which comprises reacting 2-methoxy phenol with epichlorohydrin in the presence of a base in water without using organic solvent and optionally in the presence of a phase transfer catalyst.
In yet another embodiment, the present invention provides a process for the preparation of highly pure iV-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV,
(Formula Removed)
Formula IV
which comprises reacting 2-chloro-N-(2,6-dimethylphenyl)acetamide with piperazine in the presence of a suitable base in a suitable solvent.
In further embodiment, the present invention provides highly pure N-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV having XRD pattern similar as given in Fig 1 and DSC as given in Fig.4.
In yet another embodiment, the present invention provides a process for the preparation of ranolazine in high yield and purity from highly pure N-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV having XRD pattern similar as given in Fig 1 and DSC as given in Fig.4.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1: X-ray powder diffraction pattern of N-(2,6-dimethyl phenyl)-1-piperazine acetamide
Fig 2: X-ray powder diffraction pattern of N-(2,6-dimethyl phenyl)-1-piperazine acetamide hydrochloride
Fig 3: X-ray powder diffraction pattern of mixture of N-(2,6-dimethyl phenyl)-1-piperazine acetamide and N-(2,6-dimethyl phenyl)-1-piperazine acetamide hydrochloride
Fig 4: DSC of N-(2,6-dimethyl phenyl)-1-piperazine acetamide
Fig 5: DSC of N-(2,6-dimethyl phenyl)-1-piperazine acetamide hydrochloride
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a cost effective and industrially advantageous process for the preparation of ranolazine of formula I in high yield and high purity,
(Formula Removed)
Formula I
by condensing l-methoxy-2-(oxiranylmethoxy)benzene of formula II and N-(2,6-
dimethyl phenyl)-1-piperazine acetamide of formula IV in the presence of suitable
solvent.
One embodiment of the present invention provides an improved and efficient
process for preparing l-methoxy-2-(oxiranylmethoxy)benzene of formula II, an
important intermediate for the preparation of ranolazine.

(Formula Removed)
Formula II
Generally, the reaction of 2-methoxyphenol with epichlorohydrin is carried out in the presence of a base in water and optionally in the presence of a phase transfer catalyst.
Typically, the process involves reacting 2-methoxyphenol with epichlorohydrin and at least one base in water without adding any solvent and optionally in the presence of a phase transfer catalyst, it is only until the work up phase, i.e. after the reaction has taken place, the solvents are added to the reaction mixture. Generally, the reaction mixture is stirred for few minutes to few hours at 20-100 °C. Preferably, the reaction mixture is stirred for 4 to 6 hours at 25-35 °C. The reaction completion is monitored by thin layer chromatography/high performance liquid chromatography. After completion of reaction, layers are separated and the aqueous layer is extracted with suitable solvent such as toluene. The combined organic layer is optionally charcoalized and distilled under vacuum to afford 1-methoxy-2-(oxiranylmethoxy)benzene free from other corresponding isomeric impurities, which can be used as such in next step.
(Formula Removed)
Typically, bases include, but are not limited to alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide and the like. Preferably, the base is sodium hydroxide.
The phase transfer catalyst may be present in an amount of about 0.05 to about 1.0 mol, preferably 0.05 to 0.5 mol equivalents to 2-methoxyphenol, and is most preferably present in an amount of about 0.05 to about 0.18 mol equivalents to 2-methoxyphenol. Several classes of compounds are known to be capable of acting as phase transfer catalysts, such as quaternary ammonium compounds viz: benzyl trimethylammonium chloride and bromide, phosphonium compounds or synthetic resins. Phase transfer catalysts include, but are not limited to, tetrabutylammonium bromide or chloride; benzyltriethylammonium chloride; tetrabutylammonium hydroxide; tricaprylylmethylammonium chloride, dodecyl sulfate, sodium salt, such as sodium lauryl sulfate; tetrabutylammonium hydrogensulfate; hexadecyltributylphosphonium bromide; hexadecyltrimethyl

ammonium bromide or resin amberlite IRA-410. Preferably, the phase transfer catalysts used in the method of the present invention include at least one of the benzyltriethylammonium chloride or resin amberlite IRA-410.
Optionally, crude l-methoxy-2-(oxiranyl methoxy)benzene may be purified using high vacuum distillation at 130-150 °C at 4-5 bar pressure to afford highly pure 1-methoxy-2-(oxiranylmethoxy)benzene.
Yet another key intermediate, 2-chloro-N-(2,6-dimethylphenyl) acetamide of formula III,
(Formula Removed)
Formula III
can be prepared by the processes reported in prior art such as US patent 4,567,264, PCT publication WO 2008/047388 or as exemplified herein for reference.
Typically, the process comprises reacting 2,6-dimethylaniline with chloroacetyl chloride in the presence of a base in a suitable solvent. Particularly, 2,6-dimethylaniline is reacted with chloroacetyl chloride in the presence of a base in water, water miscible solvent and mixtures thereof. Preferred water miscible solvents are selected from tetrahydrofuran, acetonitrile, dimethylformamide, methanol, ethanol, isopropanol, acetone and the like. Typically, inorganic bases include, but are not limited to alkali metal hydroxides, carbonates and bicarbonates. The alkali metal hydroxides, carbonates, and bicarbonates may include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate; preferably the base is sodium bicarbonate. The reaction is
performed at a temperature of below 10 °C and it takes about 2 to 5 hours for completion of reaction.
Another embodiment of the present invention provides an improved process for the preparation of N-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV
(Formula Removed)
Formula IV
by condensing 2-chloro-iV-(2,6-dimethylphenyl)acetamide of formula III with piperazine in the presence of a suitable base in a suitable solvent.
Particularly, the piperazine may be present in an amount of about 1.1 to about 3.5 mol, preferably 2.2 to 3.5 mol equivalents to 2-chloro-N-(2,6-dimethylphenyl)acetamide. Piperazine can be present in hydrous or anhydrous form. The reaction results in the formation of hydrochloric acid as a by-product during this condensation reaction. It is advantageous to use a suitable base in place of excess amount of piperazine to neutralize the hydrochloric acid. Further, it is observed that excess piperazine if not completely removed may react with compound of formula II to form following impurities of formula V and formula VI.
Formula V
(Formula Removed)
Formula VI
The removal of these impurities is difficult and may require additional purification steps, therefore use of limited amount of piperazine is beneficial.
Typically, the compound of formula III is condensed with piperazine in the presence of a base in a suitable solvent. Base can be selected from inorganic bases or organic bases. Inorganic base include, but not limited to ammonia, alkali metal hydroxides, carbonates and bicarbonates such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate. Organic base include but not limited to a group of general formula NHR1R2 or NR1R2R3, wherein Ri, R2 and R3 are independently selected from a (Ci-C6)-alkyl; a cycloalkyl-(Ci-C3); a phenyl which is unsubstituted or monosubstituted or polysubstituted; a naphthyl; an anthracenyl; a saturated 5- to 8-membered heterocyclic radical which is unsubstituted or substituted by a (C| -C3)- alkyl with the proviso thet the hetero cyclic radical is not piperazine. Preferably the organic base is selected from N,N-diisopropylethyl amine, triethylamine, pyridine and the like.
Solvents include, but not limited to alcohols such as ethanol, methanol, isopropanol, isoamyl alcohol; hydrocarbons such as toluene; nitrile like acetonitrile; ether such as tetrahydrofuran; ketones such as methylisobutyl ketone, acetone; water, dimethylforrnamide, dimethylsulfoxide, dioxane and the like or mixture thereof.
The reaction is conducted at 20-80 °C and it takes upto 20 hours for completion of reaction. Preferably, the reaction is conducted at 40-80 °C and it takes 1-3 hours for completion of reaction. The progress of reaction is the monitored by thin layer chromatography/high performance liquid chromatography. After
completion of reaction, the reaction mass is cooled to ambient temperature, diluted with water and filtered. The filtrate is extracted with halogenated solvents such as dichloromethane or chloroform or dichloroethane. The organic layer obtained is washed with water and the solvent may be optionally removed using techniques commonly known to one skilled in the art or proceeded for the next step as such without isolating the formula IV. The solvent is preferably removed by distillation from the reaction mixture under vacuum or atmospheric pressure to obtain pureN-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV in high yield.
We have observed that compound of formula IV forms its hydrochloride salt in the presence of methylene chloride during distillation step. Once hydrochloride salt formation occurs, it is difficult to hydrolyse it to free amine. Further, it is found that presence of hydrochloride salt of compound of formula IV, during the condensation of compound of formula II and compound of formula IV results in the formation of lot of impurities. Besides this, hydrochloride salt of compound of formula IV does not react with compound of formula II, thus needs purification for the removal and hence results in low yield and increases the cost of the product, it is therefore essential to suppress the formation of hydrochloride salt formation.
In literature also it is reported that methylene chloride forms quaternary ammonium salts with amines at ambient temperature. It is advantageous to add another organic solvent in methylene chloride to minimize the formation of hydrochloride salt. Organic solvent include, but not limited to alcoholic solvent, DMSO. Although chloroform is a class I solvent and is not a solvent of choice due to its carcinogenicity, but compound of formula does not form its hydrochloride salt in chloroform, therefore chloroform may also be used as solvent of choice during this work up. The compound of formula IV is isolated in pure crystalline form and is having XRD as shown in Fig. 1 and DSC as shown in Fig. 4.
We have isolated the pure hydrochloride salt of formula IV which is formed during the workup and is having XRD as shown in Fig. 2 and DSC as shown in Fig. 5. Alternatively, the formation of salt can be suppressed by the presence of any base viz. alkali metal carbonate or bicarbonate otherwise the yield of ranolazine will be less due to the formation of more impurities which needs purification.
The present invention is advantageous as it teaches the process for the preparation of 1 -methoxy-2-(oxiranylmethoxy)benzene of formula II, in the presence of water without using any organic solvent. Thus process is avoiding use of organic solvents and hence process is cost effective and environment friendly. Further, the use of an inexpensive base instead of adding an excess of piperazine makes the process appealing from cost point of view.
Yet another embodiment of the present invention provides a process for the preparation of ranolazine of formula I by the condensation of l-methoxy-2-(oxiranyl methoxy) benzene of formula II and N-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV in a suitable solvent.
Suitable solvent includes, but not limited to water, halogenated solvents, alcohols, nitriles, esters, ethers, ketones, hydrocarbons or mixture thereof.
Preferably, l-methoxy-2-(oxiranyl methoxy) benzene of formula II and N-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV in a suitable solvent are stirred at ambient temperature. Suitable solvent is selected from water, halogenated solvents, alcohols nitriles, esters, ethers, ketones, hydrocarbon or mixture thereof. Thereafter, the reaction mass is refluxed preferably till reaction completion. The progress of reaction is monitored by thin layer chromatography/high performance liquid chromatography. After completion of reaction, the reaction mixture is cooled to ambient temperature followed by further cooling to a temperature of below 15 °C to form ranolazine which can be isolated by methods well known in art preferably by filtration.
If required, ranolazine so formed can further be purified by washing with suitable solvent or by recrystallization with suitable solvent such as alcohols or aromatic hydrocarbons to obtain highly pure ranolazine having purity greater than 99% area by HPLC in high yield. Further ralolazine can be purified by converting it to an acid addition salt of ranolazine and further hydrolyzing the acid addition salt to ranolazine. The acid used for the preparation of acid addition salt include but not limited to hydrochloric, hydrobromic, sulfuric, phosphoric, oxalic, citric, tartaric, succinic, fumaric, maleic, acetic and similar acids.
The order and manner of combining the reactants at any stage of the invention are not important and may be varied. The reactants may be added to the reaction mixture as solids, or may be dissolved individually and combined as solutions. Further any of the reactants may be dissolved together as sub-groups, and those solutions may be combined in any order.
The present invention will now be illustrated by the following examples, which are not intended to limit the effective scope of the claims. Consequently, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as claimed. The present invention has been described in terms of its specific embodiments and various modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of present invention.
EXAMPLES
Example 1
Step 1: Preparation of l-methoxv-2-(oxiranvlmethoxv)benzene
Process-A
To a solution of sodium hydroxide (40g, l.Omol) in demineralized water (800 ml), 2-methoxyphenol (lOOg, 0.80mol) and benzyltriethylammonium chloride (30g,
0.13mol) were added at 25-30 °C and stirred for 30 minutes. Epichlorohydrin (lOOg, 1.08mol) was added slowly to the above reaction mixture at 25-30 °C. The reaction mass was then allowed to stir for 5 hours at 25-30 °C. After completion of reaction (monitored by thin layer chromatography), the reaction mass was extracted twice with toluene and the combined organic layer was washed with water. The^ solvent was distilled under vacuum to give the product as oil which was purified by high vacuum distillation to give 103g (Yield = 71.0%) of the title compound having purity 96.44% by high performance liquid chromatography.
Process-B
To a solution of sodium hydroxide (4g, 0.1 mol) in demineralized water (40ml) and 2-methoxyphenol (lOg, 0.08mol), epichlorohydrin (lOg, O.llmol) and resin Amberlite IRA-410 (6.4g, 10% of total weight) were added at 25-30 °C and the reaction mass was allowed to stir for 5 hours at the same temperature. After completion of reaction (monitored by thin layer chromatography), the reaction mass was extracted twice with toluene and the combined organic layer was washed with water. The solvent was distilled under vacuum to give the product as oil which was purified by high vacuum distillation to give 8.4g of title compound.
Step 2: Preparation of 2-chloro-7V-(2,6-dimethvlphenyl)acetamide
To a solution of sodium bicarbonate (120g) in 1000ml of demineralized water, tetrahydrofuran (120ml), 2,6-dimethylaniline (lOOg, 0.82mol) and chloroacetyl chloride (106g, 0.94mol) were added at 0 to 5 °C. The reaction mass was then stirred for 3 hours at 0 to 5 °C. After completion of reaction (monitored by thin layer chromatography), the reaction mass was filtered, washed with demineralized water (500ml) and hexane (200ml) to give 151g (Yield = 92.6%) of the title compound as an off white solid having purity 99.74% by high performance liquid chromatography.
Step 3: Preparation of N(2,6-dimethyl phenvD-1-piperazine acetamide
Process-A
A stirred mixture of 2-chloro-N-(2,6-dimethylphenyl)acetamide (25g, 0.13mol), piperazine (25g, 0.29mol) and potassium carbonate (25g, 0.18mol) in ethanol (75ml) was refluxed for 1 hour at 78-80 °C. After completion of reaction (monitored by thin layer chromatography), the reaction mass was diluted with demineralized water (200ml), cooled and filtered. The total filtrate was extracted with dichloromethane. The combined organic layer was washed with demineralized water and solvent was distilled completely to give 27.2g (Yield = 86.4%) of title compound having purity 98.2% by high performance liquid chromatography.
Process-B
A mixture of 2-chloro-N-(2,6-dimethylphenyl)acetamide (25g, 0.13mol) and piperazine (36g, 0.42mol) in ethanol (75ml) was refluxed for 3 hours at 78-80 °C. After completion of reaction (monitored by thin layer chromatography), the reaction mass was diluted with demineralized water (200ml) and reaction mass was cooled to 10 °C and filtered. The pH of the filtrate was adjusted to 11.0 with aq. ammonia solution and extracted with dichloromethane. The combined organic layer was again washed with 10% aqueous ammonia solution, demineralized water and distilled to give 28g (Yield = 89.6%) of title compound having purity 97.11% by high performance liquid chromatography.
Process-C
A mixture of 2-chloro-N-(2,6-dimethylphenyl)acetamide (lOg, 0.05mol) and piperazine hexahydrate (40g, 0.20mol) in ethanol (30ml) was refluxed for 3 hours. After completion of reaction (monitored by thin layer chromatography), the reaction mass was diluted with demineralized water (80ml) and the reaction mass was cooled to 5-10 °C and filtered through hyflo bed, and the filtrate was
extracted with dichloromethane. The combined organic layer was washed with 5% aqueous sodium hydroxide solution, demineralized water and distilled to give 10.5g (Yield = 84%) of title compound having purity 98.32% by high performance liquid chromatography.
Step 4: Preparation of Ranolazine
Process-A
A stirred mixture of 2-chloro-N-(2,6-dimethylphenyl)acetamide (25g, 0.13mol), piperazine (25g, 0.29mol) and potassium carbonate (25g, 0.18mol) in ethanol (75ml) was refluxed for 1 hour at 78-80 °C. After completion of reaction (monitored by thin layer chromatography), the reaction mass was diluted with demineralized water (200ml), cooled and filtered. The total filtrate was extracted with dichloromethane. The combined organic layer was washed with demineralized water and solvent was distilled completely to give 27.2g solid which was taken in ethanol (175ml), l-methoxy-2-(oxiranylmethoxy)benzene (20g, O.llmol) was added at 25 to 30 °C to the reaction mass and the reaction mass was refluxed for 3 hours. After completion of reaction (monitored by thin layer chromatography), the reaction mass was charcoalised. The filtrate was cooled to 5 to 10 °C, stirred for 3 hours at the same temperature. The crystallized product was filtered, washed with chilled ethanol (25ml) and dried to give 38g of title compound as a white solid having purity 99.54% by high performance liquid chromatography.
Process-B
7V-(2,6-dimethylphenyl)-l-piperazine acetamide (lOg, 0.04mol), water (50ml) and l-methoxy-2-(oxiranylmethoxy)benzene (8g, 0.04mol) were refluxed for 3 hours. After completion of reaction (monitored by thin layer chromatography), the reaction mass was cooled to 25-30 °C and stirred for 3 hours. The precipitated product was filtered, washed with water and recrystallized from ethanol to give 1 Og of the title compound as white solid.
Process-C
A stirred mixture of 2-chloroN-(2,6-dimethylphenyl)acetamide (50g, 0.26mol), piperazine (50g, 0.58mol) and potassium carbonate (50g, 0.36mol) in ethanol (150ml) was refluxed for 1 hour at 78-80 °C. After completion of reaction (monitored by thin layer chromatography), the reaction mass was diluted with demineralized water (400ml), cooled and filtered. The total filtrate was extracted with chloroform. The combined organic layer was washed with demineralized water and solvent was distilled completely to give 56g solid which was taken in ethanol (350ml), l-methoxy-2-(oxiranylmethoxy)benzene (40g, 0.22mol) was added at 25 to 30 °C to the reaction mass and the reaction mass was refluxed for 3 hours. After completion of reaction, the reaction mass was charcoalised. The filtrate was cooled to 5 to 10 °C, stirred for 3 hours at the same temperature. The crystallized product was filtered, washed with chilled ethanol (50ml) and dried to give 70.5g of title compound having purity 99.33% by HPLC
Process-D
A stirred mixture of 2-chloro-Ar-(2,6-dimethylphenyl)acetamide (25g, 0.13mol), piperazine (25g, 0.29mol) and potassium carbonate (25g, 0.18mol) in ethanol (75ml) was refluxed for 1 hour at 78-80 °C. After completion of reaction (monitored by thin layer chromatography), the reaction mass was diluted with demineralized water (200ml), cooled and filtered. The total filtrate was extracted with dichloromethane. The combined organic layer was washed with demineralized water and organic layer was diluted with ethanol (200ml), 1-methoxy-2-(oxiranylmethoxy)benzene (20g, 0.1 lmol) was added at 25 to 30 °C to the reaction mass and the reaction mass was stirred at 60-65 °C for 3 hours. After completion of reaction, the reaction distilled to give a residue which was diluted with ethanol (175ml) and charcoalised. The filtrate was cooled to 5 to 10 "C, stirred for 3 hours at the same temperature. The crystallized product was filtered, washed with chilled ethanol (25ml) and dried to give 37g of title compound as a white solid having purity 99.04% by HPLC.

WE CLAIM
1. A process for the preparation of l-[3-(2-methoxyphenoxy)-2-hydroxy propyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine (Ranolazine) of formula I,

(Formula Removed)
Formula I
comprises the steps of:
a. reacting 2-methoxyphenol with epichlorohydrin in the presence of a base in a
suitable solvent preferably water without using organic solvent and optionally
a phase transfer catalyst to afford 1 -methoxy-2-(oxiranyl methoxy)benzene of
formula II,
(Formula Removed)
Formula II
b. reacting 2,6-dimethylaniline with chloroacetyl chloride in the presence of base
in water, optionally in the presence of water miscible solvent to afford 2-chloro-N-(2,6-dimethylphenyl)acetamide of formula III,

(Formula Removed)
c. reacting 2-chloro-N(2,6-dimethylphenyl)acetamide with piperazine in the presence of a suitable base in a suitable solvent to form N-(2,6-dimethyl phenyl)-!-piperazine acetamide of formula IV, and
(Formula Removed)
Formula IV
d. condensing N-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV with l-methoxy-2-(oxiranyl methoxy)benzene of formula II in suitable solvent to form ranolazine.
2. The process according to claim 1, wherein in step a, base is alkali metal hydroxide and phase transfer catalyst is benzyltriethylammonium chloride, resin amberlite IRA-410 and the like.
3. The process according to claim 1, wherein in step b, base is alkali metal carbonate or bicarbonate or alkali metal hydroxides and water miscible solvent is selected from tetrahydrofuran, acetonitrile, dimethylformamide, methanol, ethanol, isopropanol, acetone and the like or mixture thereof.
4. The process according to claim 1, wherein in step c, wherein base is selected from inorganic base and organic base; a suitable solvent includes alcohols such as ethanol, methanol, isopropanol, isoamyl alcohol; hydrocarbons such as toluene; nitrile such as acetonitrile; ether such as tetrahydrofuran, methyl tertiary butyl ether, isopropyl ether; ketones such as methylisobutyl ketone, acetone; water, dimethylformamide, dimethylsulfoxide, 1,4-dioxane and the like or mixture thereof.
5. The process according to claim 1, wherein in step d, suitable solvent is selected
from water, halogenated solvents, alcohols, nitriles, esters, ethers, ketones, hydrocarbons and mixture thereof.
6. A process for the preparation of l-methoxy-2-(oxiranyl methoxy) benzene of formula II,
(Formula Removed)
Formula II
which comprises:
reacting 2-methoxyphenol with epichlorohydrin in the presence of a base in water without using organic solvent and optionally a phase transfer catalyst.
7. The process according to claim 6, wherein base includes alkali metal hydroxide
and the phase transfer catalyst includes quaternary ammonium compounds and phosphonium compounds; preferably benzyltriethylammonium chloride, resin amberliteIRA-410.
8. A process for the preparation of of N-(2,6-dimethyl phenyl)-1-piperazine
acetamide of formula IV,
(Formula Removed)
Formula IV
which comprises:
reacting 2-chloro-JV-(2,6-dimethylphenyl)acetamide with piperazine in the presence of a suitable base in a suitable solvent.
9. The process according to claim 8, wherein a suitable base include an inorganic base or an organic base.
10. A process for the preparation of l-[3-(2-methoxyphenoxy)-2-hydroxy propyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine (Ranolazine) of formula I, (Formula Removed)
Formula I
comprises condensing pure N-(2,6-dimethyl phenyl)-1-piperazine acetamide of formula IV having XRD as shown in Fig 1 and DSC as shown in Fig 4, with l-methoxy-2-(oxiranyl methoxy)benzene of formula II in a suitable solvent to form ranolazine.

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Patent Number

279966

Indian Patent Application Number

1517/DEL/2008

PG Journal Number

06/2017

Publication Date

10-Feb-2017

Grant Date

06-Feb-2017

Date of Filing

24-Jun-2008

Name of Patentee

IND-SWIFT LABORATORIES LIMITED

Applicant Address

S.C.O. NO. 850, SHIVALIK ENCLAVE, NAC MANIMAJRA, CHANDIGARH-160 101 INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	CHIDAMBARAM VENKATESWARAN SRINIVASAN	E-5, PHASE II, INDUSTRIAL AREA, MOHAL-160 055 PUNJAB, INDIA
2	AGGARWAL ASHVIN KUMAR	E-5, PHASE II, INDUSTRIAL AREA, MOHAL-160 055 PUNJAB, INDIA.
3	JAIN ANSHUL KUMAR	E-5, PHASE II, INDUSTRIAL AREA, MOHAL-160 055 PUNJAB, INDIA
4	WADHWA LALIT	E-5, PHASE II, INDUSTRIAL AREA, MOHAL-160 055 PUNJAB, INDIA

PCT International Classification Number

C07D

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA