Field of the Invention:

The present invention relates to novel processes for the preparation of ranolazine (I) to yield ranolazine with high purity.

Background of the Invention:

Ranolazine (I), chemically known as N-(2,6-dimethyl phenyl)-4-[2-hydroxy-3-(2-methoxy phenoxy) propyl] -1-piperazine acetamide, is useful as antianginal agent. Ranolazine is indicated for the treatment of chronic anginal. Ranolazine has been reported to protect against biochemical electrophysiological and thermodynamic consequences of transient myocardial ischmia. Ranolazine has been shown to exert anti-anginal and anti-ischemic effects without reducing heart rate or blood pressure. It does not increase the rate-pressure product at maximal exercise levels. Ranolazine is represented by the formula (I) as given below.

(I)

Ranolazine was first disclosed in product patent US 4,567,264 which also describes its preparation by condensing N-(2,6-dimethylphenyl)-l-piperazineacetamide (II) with l-(2- methoxyphenoxy)2,3-epoxypropane (III) (scheme I). The ranolazine was obtained in 75-80% purity, which was further purified by column chromatography and was isolated as an oil. Methanol-Toluene Reflux

(I)

(II)

Scheme I

The patent EP 0483932 describes the preparation of ranolazine base by condensation of alpha-[N,N-bis(2-chloroethyl)-amino]-2,6-dimethylacetanilide (IV) with l-[3-(2-methoxy phenoxy)-2-hydroxy] -propylamine (V) as described in scheme (II). The crude ranolazine was further purified by column chromatography and is isolated as an oil.

Scheme Il

The PCT application WO 2008/ 139492 describes same process for the preparation of ranolazine as described in product patent US 4567264. It further describes purification method that involves preparation of acid addition _, salt of ranolazine with fumaric acid, crystallization of the salt obtained followed by neutralization to give pure ranolazine.

The publication, Moen et al, Biocatalysis and Biotransformation, January-February 2005, 23 (1); 45-51 describes the purification of ranolazine by flash chromatography using methanol- ether as a solvent.

The PCT application WO 2008/047388 describes the crystallization methods for ranolazine base from alcohols or aromatic hydrocarbons. The most preferred alcohol being ethanol and the most preferred aromatic hydrocarbon being toluene. The purity of pure ranolazine obtained by crystallization is 99.49%.

The prior art methods discussed above suffer from the following disadvantages: a) the ranolazine is obtained as an oil is difficult to handle on large scale, b) prior art method uses fumaric acid, which makes the process multistep, increases the time cycle, decreases the yield and increases the cost. c) laborious chromatographic techniques are used for purification of ranolazine and d) crystallization methods known in the prior art provides ranolazine in relatively lower purity.

It is observed that pharmaceutically acceptable salts of ranolazine when prepared from impure ranolazine do not meet with the pharmaceutically acceptable quality. There is, therefore, an unfulfilled need to provide industrially feasible process for the preparation of ranolazine free base with higher purity. The present invention is directed for the same and provides ranolazine in purity > 99.8%.

Summary of the Invention:

The present invention is related to a novel process for the preparation of ranolazine (I), having purity > 99.8% that comprises the following steps:

(i) reaction of 2,6-xylidine (VI) with chloroacetyl chloride (VII) in the presence of base to give chloroacetamide (VIII), (ii) reaction of chloroacetamide (VIII) with piperazine to give piperazine acetamide

(H) ₅ (iii) reaction of piperazine acetamide (II) with epoxide (III) to give ranolazine,

(iv) purification of ranolazine by crystallization from ketonic solvent or mixture of ketonic solvent and other organic solvent. Description of the Drawings:

Figure 1: X-ray powder diffractogram (XRPD) for crystalline form of ranolazine obtained by the process of the present invention.

Figure 2: IR spectrum for crystalline form of ranolazine obtained by the process of the present invention.

Detailed description of the invention:

The present invention is related to a novel process for the preparation of ranolazine (I) as described in scheme (III), having purity > 99.8% that comprises the following steps: ^'

(i) reaction of 2,6-xylidine (VI) with chloroacetyl chloride (VII) in the presence of base to give chloroacetamide (VIII),

(ii) reaction of chloroacetamide (VIII) with piperazine to give piperazine acetamide (II),

(iii) reaction of piperazine acetamide (II) with epoxide (III) to give ranolazine,

(iv) purification of ranolazine by crystallization from ketonic solvent or mixture of ketonic solvent and other organic solvent.

The synthetic scheme of the process of present invention is shown in scheme III

Scheme III The process of step 1 comprises of reaction of 2,6 xylidine (VI) with chloroacetyl chloride (VII) in the presence of base and a solvent to give chloroacetamide (VII).

The base used in step 1 is selected from a group of carbonates or hydroxides of alkali earth metals. The base used in step 1 is preferably selected from a group comprising of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. The most preferred base is potassium carbonate.

The process of step 1 of the present invention can be carried out in water miscible organic solvent that include tetrahydrofuran, 1,4-dioxane, dimethylforarnide, N-methyϊ-pyrrolidone, acetonitrile, propionitrile, acetone, ethylmethyl ketone and mixtures thereof. The most preferred solvent is acetone.

The process of step 2 comprises of reaction of chloroacetamide (VII) with piperazine to give piperazine acetamide (II).

The process of step 2 of the present invention can be carried out in an organic solvent that include aromatic hydrocarbons like benzene, toluene and xylene; esters like ethyl acetate and isopropyl acetate; ethers such as ethyl ether, methyl t-butyl ether, di-isopropyl ether and tetrahydrofuran; amides such as formamide, dimethylforamide and N-methyl.-pyrrolidone; nitriles such as acetonitrile and propionitrile; chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform and mixtures thereof. The most preferred solvent is isopropyl alcohol.

The process of step 3 comprises of reaction of piperazine acetamide (II) with epoxide compound (III) to give ranolazine in the presence of organic solvent.

The process of step 3 of the present invention can be carried out in an organic solvent that include aromatic hydrocarbons like benzene, toluene and xylene; esters like ethyl acetate and isopropyl acetate; ethers such as ethyl ether, methyl t-butyl ether, di-isopropyl ether and tetrahydrofuran; amides such as formamide, dimethylforamide and N-methyl-pyrrolidone; nitriles such as acetonitrile and propionitrile; ketones such as acetone and ethylmethyl ketone; chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform and mixtures thereof. The most preferred solvent mixture is toluene-methanol.

The process of step 3 can be optionally carried out in the presence of silica (60-120 mesh).

The step 4 involves purification of crude ranolazine free base which is obtained as oily product. The purification method involves treating oily ranolazine with a ketonip solvent or a mixture of ketonic solvent and other organic solvent.

The ketonic solvent is selected from a group comprising of acetone, propanone, butanone, methyl ethyl ketone etc. The most preferred ketonic solvent is acetone.

The other organic solvent of step 4 includes hydrocarbons such as cyclohexane, cycloheptane, cyclopentane, benzene toluene xylene, esters such as ethyl acetate, isopropyl acetate, alcohols such as ethanol, butanol, isopropanol and methanol.

The preferred other organic solvent of step 4 includes cyclohexane, ethyl acetate, isopropanol and methanol.

The purity of ranolazine free base (I) obtained by the process of the present invention is > 99.8%.

The crystalline form of ranolazine obtained by the process of the present invention is characterized by XRPD pattern as shown in figure 1. The characteristic peaks in XRPD of ranolazine are as shown in table 1. Table 1: XRPD of crystalline form of ranolazine

The crystalline ranolazine free base described herein is further identified by IR spectrum as shown in figure 2. The IR spectrum of crystalline ranolazine free base described herein has characteristic bands at 3330.31, 2833.68, 1686.06, 1592.04, 1223.86, 1253.59, 769.95,

742.11 cm ^"1 . The melting point of the obtained ranolazine free base lies in the range of 119-Ϊ21°C.

The particle size (micrometer) of ranolazine free base obtained by the present invention is dio: 0.5-11; d ₅₀ : 15-35; d ₉₀ : 35-70

The aforementioned process for the preparation of ranolazine (I) has the following advantages: i) purity of ranolazine is > 99.8%, ii) simple and quick process, iii) easy to scale up, iv) economical process, v) avoids reagents like fumaric acid and vi) avoids chromatographic techniques,

The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing examples. The invention, which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.

Examples

Step 1: Preparation of chloro acetamide (VIII) 100 gm of 2,6-Xylidine (VI) was dissolved in acetone (250 ml) followed by addition of 148.2 gm Of K ₂ CO ₃ and water (500 ml). The reaction mixture was cooled 5 ⁰ C and 130.6 gm of chloro acetyl chloride (VII) was added. The reaction mass was stirred at 5-15 ⁰ C for 4 hours. Water (500 ml) was added at 5-15 ⁰ C and stirred for 1 hour. The solid was filtered, washed with acetone and dried under reduced pressure. Step 2: Preparation of Piperazine acetamide (II)

100 gm of chloro acetamide (VIII) and 172 gm of anhydrous piperazine was dissolved in 1000 ml of isopropyl alcohol. The reaction mixture was stirred for 1 hour at reflux temperature. The reaction mass was concentrated to get thick slurry and water (1000 ml) was charged to the slurry. 350 ml of 50% aqueous acetic acid solution was added to adjust pH between 5.0-5.50. The reaction mass was extracted with dichloromethane (3 x 500 ml). The aqueous layer was basified with 720 ml of 5N NaOH solution and extracted with dichloromethane (3 x 500 ml). The combined organic layer was washed with 20% brine solution. The organic layer was separated and concentrated under reduced pressure to get oily mass. Cyclohexane (300 ml) was charged to the oily mass. Stirred for 30 minutes at 45- 5O ⁰ C. Cooled to 25-3O ⁰ C and stirred for 1 hour. The solid was filtered, washed with 100 ml of cyclohexane and dried under reduced pressure to give 105 gm of white solid. '

Step 3: Preparation of ranolazine (I)

100 gm Piperazine acetamide (II) was dissolved in ^' solvent mixture comprising 500 ml of toluene and 100 ml of methanol. To this solution 109.12 gm of epoxide (III) was added. The reaction mixture was stirred at 50-55 ⁰ C till completion. The reaction mass was concentrated under reduced pressure. To the residue water (500 ml) and dichloromethane (500 ml) was added. The pH of the reaction mass was adjusted between 1-1.5 using dilute hydrochloric acid. The organic layer was separated and the aqueous layer was washed with dichloromethane (2 x 200 ml). The aqueous layer was separated and basified with 200 ml of 5N NaOH solution. Product was extracted with dichloromethane (3 x 500 ml). The combined organic layer was washed with water and 20% brine solution. The organic layer was concentrated to afford an oily product. Yield: 155 gm, HPLC purity: 98%. To the oily mass acetone (400 ml) was charged and stirred for 1 hour at 45-5O ⁰ C. The slurry was cooled to 25- 3O ⁰ C and stirred for an hour. Further cooled to 5-10 ⁰ C. The solid was filtered, washed with chilled acetone (100 ml) and dried to give crude ranolazine base as solid. Yield: 145 gm, purity 99.5%. Step 4: Purification of ranolazine (I) Example 1:

Crude ranolazine (10 gm) was added to acetone (30 ml). The mixture was heated up to 45- 5O ⁰ C and stirred for an hour. The mixture was further stirred for two hours at 25-30 ⁰ C. The solid product was filtered, washed with acetone and ^" dried to afford ranolazine. Yield : 9 gm (90%), HPLC purity: 99.80%.

Example 2: Crude ranolazine (10 gm) was added to a mixture of acetone (30 ml) and methanol (10 ml) and heated to 45-50 ⁰ C. The mixture was further stirred to 2 hours at 25-30 ⁰ C and for an hour at 15-2O ⁰ C. The solid product was filtered, washed and dried with acetone to afford pure ranolazine. Yield : 8.5 gm (85%), HPLC purity: 99.80%

Example 3:

Crude ranolazine (10 gm) was added to acetone (50. ml). The mixture was heated up to 45- 5O ⁰ C and stirred for an hour. The mixture was further stirred for two hours at 25-3O ⁰ C. The solid product was filtered, washed with acetone and dried to afford ranolazine. Yield : 8.7 gm (87%), HPLC purity: 99.83%.

Example 4:

Crude ranolazine (10 gm) was added in solvent mixture of acetone (30 ml) and isopropyl alcohol (10 ml) and stirred at 25-30 ⁰ C for an hour. The mixture was heated at 45-50 ⁰ C and then stirred for an hour at 20-25 ⁰ C. The solid product was filtered, washed with acetone and isopropyl alcohol mixture and dried to afford pure ranolazine. Yield: 8.7 gm (87%), HPLC purity 99.84%. Example 5:

Crude ranolazine (10 gm) was added to acetone (50 ml) and heated to 45-5O ⁰ C for an hour. The mixture was cooled to room temperature and stirred for an hour. The reaction was further cooled to 5-10 ⁰ C and stirred for an hour. The solid product was filtered and washed with chilled acetone (10 ml) to afford pure ranolazine. Yield: 9.3 gm (93%), HPLC purity 99.80%.

Example 6:

Crude ranolazine (10 gm) was taken in acetone (50 ml) with stiring at room temperature and heated upto 45-5O ⁰ C for an hour. The reaction mixture was cooled to room temperature and stirred for an hour. Then reaction mixture was further cooled to 10-15 ⁰ C with stirring. The solid product was filtered and washed with acetone (10 ml) to afford wet ranolazine. The wet cake was charged in ethyl acetate (30 ml) and stirred for an hour at 25-3O ⁰ C. The product was filtered, washed with ethyl acetate and dried to give pure ranolazine. Yield: 8 ^' 5 gm (85%), HPLC purity 99.85%.

Example 7:

Crude ranolazine (10 gm) was taken in acetone (50 ml) with stirring at room temperature and heated upto 45-5O ⁰ C for an hour. The mixture was cooled to room temperature and stirred for an hour. The mixture was further cooled to 10-15 ⁰ C with stirring. The solid product was filtered and washed with acetone (10 ml) to afford wet ranolazine. The wet cake was charged in cyclohexane (50 ml) and stirred for an hour at 25-3O ⁰ C. The product was filtered, washed and dried with cyclohexane to give pure ranolazine. Yield: 8.8 gm (88%), HPLC purity: 99.87%.

Example 8:

Crude ranolazine (60 gm) was taken in acetone (300 ml) with stiring at room temperature and heated upto 45-5O ⁰ C for an hour. The reaction mixture was cooled to room temperature and stirred for an hour. Then reaction mixture was further cooled to 10-15 ⁰ C with stirring. The solid product was filtered and washed with acetone (60 ml) to afford wet ranolazine. The wet cake was charged in ethyl acetate (180 ml) and stirred for an hour at 25-3O ⁰ C and then stirred for an hour at 10-15 ⁰ C. The product was filtered, washed with ethyl acetate and dried to give pure ranolazine. Yield: 53.4 gm (89%), HPLC purity 99.82%.

Example 9:

Crude ranolazine (60 gm) was taken in acetone (300 ml) with stiring at room temperature and heated upto 45-5O ⁰ C for an hour. The reaction mixture was cooled to room temperature and stirred for an hour. Then reaction mixture was further cooled to 10-15 ⁰ C with stirring. The solid product was filtered and washed with acetone (60 ml) to afford wet ranolazine. The wet cake was charged in ethyl acetate (180 ml) and stirred for an hour at 25-3O ⁰ C and then stirred for an hour at 15-20 ⁰ C. The product was filtered, washed with ethyl acetate (60 ml) and dried to give pure ranolazine. Yield: 52.59 gm (87.66%), HPLC purity 99.82%.

Example 10:

Crude ranolazine (60 gm) was taken in acetone (300 ml) with stiring at room temperature and heated upto 45-5O ⁰ C for an hour. The reaction mixture was cooled to room temperature and stirred for an hour. Then reaction mixture was further cooled to 10-15 ⁰ C with stirring. The solid product was filtered and washed with acetone (60 ml) to afford wet ranolazine. The wet cake was charged in ethyl acetate (180 ml) and stirred for an hour at 25-30 ⁰ C and then stirred for an hour at 15-2O ⁰ C. The product was filtered, washed with ethyl acetate (60 ml) and dried to give pure ranolazine. Yield: 52.59 gm (87.66%), HPLC purity 99.85%.

Example 11: Grade ranolazine (40 gm) was taken in acetone (200 ml) with stirring at room temperature and heated upto 45-5O ⁰ C for an hour. The mixture was cooled to room temperature and stirred for an hour. The mixture was further cooled to 10-15 ⁰ C with stirring. The solid product was filtered and washed with acetone (40 ml) to afford wet ranolazine. The wet cake was charged in cyclohexane (160 ml) and stirred for an hour at 45-5O ⁰ C. The mixture was further stirred for an hour at room temperature and then stirred for an hour at 15-20 ⁰ C. The product was filtered, washed and dried with cyclohexane (40 ml) to give pure ranolazine. Yield: 35.5 gm (88.75%), HPLC purity: 99.89%.

Example 12:

Crude ranolazine (30 gm) was taken in acetone (150 ml) with stirring at room temperature and heated upto 45-5O ⁰ C for an hour. The mixture was cooled to room temperature and stirred for an hour. The mixture was further cooled to 10-15 ⁰ C with stirring. The solid product was filtered and washed with acetone (30 ml) to afford wet ranolazine. The wet cake was charged in cyclohexane (120 ml) and stirred for an hour at 45-5O ⁰ C. The mixture was further stirred for an hour at room temperature and then stirred for an hour at 15-20 ⁰ C. The product was filtered, washed and dried with cyclohexane (30 ml) to give pure ranolazine. Yield: 26.6 gm (88.75%), HPLC purity: 99.89%.

Example 13:

Crude ranolazine (50 gm) was taken in acetone (200 ml) with stirring at room temperature and heated upto 45-5O ⁰ C for an hour. The mixture was cooled to room temperature and stirred for an hour. The mixture was further cooled to 10-15 ⁰ C with stirring. The solid product was filtered and washed with acetone (40 ml) to afford wet ranolazine. The wet cake was charged in cyclohexane (200 ml) and stirred for an hour at 45-5O ⁰ C. The mixture was further stirred for an hour at room temperature and then stirred for an hour at 15-20 ⁰ C. The product was filtered, washed and dried with cyclohexane (50 ml) to give pure ranolazine. Yield: 45.3 gm (90.6%), HPLC purity: 99.90%.