WO2010023687A2 - Préparation de la ranolazine, ses sels et des intermédiaires de ceux-ci - Google Patents

Préparation de la ranolazine, ses sels et des intermédiaires de ceux-ci Download PDF

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Publication number
WO2010023687A2
WO2010023687A2 PCT/IN2009/000463 IN2009000463W WO2010023687A2 WO 2010023687 A2 WO2010023687 A2 WO 2010023687A2 IN 2009000463 W IN2009000463 W IN 2009000463W WO 2010023687 A2 WO2010023687 A2 WO 2010023687A2
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dimethylphenyl
ranolazine
formula
acetamide
piperazine
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PCT/IN2009/000463
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English (en)
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WO2010023687A3 (fr
Inventor
Thota Giridhar
Gudipati Srinivasulu
Kotaru Srinivasa Rao
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Shodhana Laboratories Limited
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Publication of WO2010023687A2 publication Critical patent/WO2010023687A2/fr
Publication of WO2010023687A3 publication Critical patent/WO2010023687A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the present patent application relates to an improved process for the preparation of Ranolazine, pharmaceutically acceptable salts and intermediates thereof. Specifically it relates to process for the preparation of l ⁇ (2-methoxy phenoxy)-2,3-epoxy propane and N-(2,6-dimethylphenyl)-l- piperazine acetamide, useful intermediates in the preparation of Ranolazine and pharmaceutically acceptable salts thereof.
  • Ranolazine is chemically described as 1 -piperazineacetamide, N-(2, 6- dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]- ) ( ⁇ ) - and is represented by the structural Formula I.
  • Ranolazine has antianginal and anti-ischemic effects that do not depend upon reductions in heart rate or blood pressure and is marketed under the trade name Ranexa. It is available for oral administration as film- coated, extended-release tablets containing 500 mg or 1000 mg of Ranolazine.
  • US Patent No 4,567,264 discloses Ranolazine, pharmaceutically acceptable esters and acid addition salts thereof and their use in the treatment of cardiovascular diseases, including arrhythmias, variant and exercise induced angina and myocardial infraction.
  • the '264 patent also discloses, among others, a process for the synthesis of Ranolazine involving reaction of l-[3-(2-rnethoxyphenoxy)-2- hydroxypropyl]-piperazine with [(2, 6-dimethylphenyl) aminocarbonylmethyl]- chlorid ⁇ in dimethylformamide to provide Ranolazine as an oil, which is purified by column chromatography and then crystallized by using hydrochloric acid in methanol.
  • PCT Application Publication No WO 2008/ 047388 discloses a process for the preparation of l-(2-methoxy phenoxy)-2, 3-epoxy propane by reacting 2-methoxyphenol with epichlorohydrin in presence of aqueous base in an organic solvent using phase transfer catalyst. It also discloses preparation of 2-chloro-N-(2,6-dimethylphenyl)acetamide by reacting 2,6-dimethylaniline with chloroacetylchloride in presence of base in water optionally in an organic solvent.
  • the aforesaid processes involve use of mixture of solvents and base such as triethylamine which is carcinogenic, making the processes expensive and not suitable for commercial manufacturing.
  • the present patent application relates to a process for the preparation of Ranolazine or a pharmaceutically acceptable salt thereof comprising the steps of:
  • step (b) reacting the 1 -(2-methoxy phenoxy)-2,3-epoxy propane of Formula IV obtained in step (a) with N-(2,6-dimethylphenyl)-l-piperazine acetamide of Formula VII to form Ranolazine.
  • the present patent application includes preparation of 1 -(2-methoxy phenoxy)-2,3-epoxy propane of Formula IV by reacting 2-methoxy phenol of Formula II with l-halo-2,3 epoxy propane of Formula III in presence of a base in substantially aqueous solvent medium, where in the base is added in lot wise or continuously over a period of time.
  • the present patent application provides a process for the preparation of N-(2,6-dimethylphenyl)-l-piperazine acetamide of Formula VII which includes: (a) reacting 2,6-dimethylaniline Formula V with chloroacetylchloride in a solvent without any added base to give 2-chloro-N-(2,6-dimethylphenyl) acetamide of Formula VI; and
  • Formula V Formula VI (b) reacting 2-chloro-N-(2,6-dimethylpherryl)acetamide of Formula VI obtained in step (a) with piperazin ⁇ or a salt thereof in a solvent.
  • the present patent application includes preparation of N-(2,6- dimethylphenyl)-l-piperazine acetamide of Formula VII which includes reaction of 2-chloro-N-(2,6-dimethylphenyl)acetamide of Formula VI with piperazine or a salt thereof in a solvent medium comprising methanol.
  • the present patent application provides three novel crystalline forms of N-(2,6-dimethylphenyl)-i -piperazine acetamide of Formula VII and processes for the preparation thereof.
  • the present application also relates to use of l-(2-methoxy phenoxy)- 2,3-epoxy propane of formula IV and N-(2,6-dimethylphenyl)-l-piperazine acetamide of formula VII in the synthesis of active pharmaceutical ingredients including Ranolazine.
  • Fig 1 is an illustrative X-ray powder diffraction pattern of Ranolazine crystalline Form 'S' obtained in Example 12.
  • Fig 2 is an illustrative XRPD pattern of N-(2,6-dimethylphenyl)-l- piperazine acetamide crystalline Form I of obtained in Example 7.
  • Fig 3 is an illustrative XRPD pattern of N-(2,6-dimethylphenyl)-l- piperazine acetamide crystalline Form II of obtained in Example 8.
  • Fig 4 is an illustrative XRPD pattern of N-(2,6-dimethylphenyl)- l- piperazine acetamide crystalline Form III of obtained in Example 9.
  • the present application relates to a process for the preparation of Ranolazine or a pharmaceutically acceptable salt thereof comprising the steps of: a) reacting 2-methoxy phenol of Formula II with l-halo-2,3 epoxy propane of Formula III in presence of a base in substantially aqueous solvent medium;
  • Formula IV Formula VII l-halo-2,3 epoxy propane used in the process of step a) is selected from l-chloro-2,3 epoxy propane, l-bromo-2,3 epoxy propane, l-fluoro-2,3 epoxy propane, l-iodo-2,3 epoxy propane, preferably l-chloro-2,3 epoxy propane (epichlorohydrin)
  • "Substantially aqueous solvent medium” as used herein refers to solvent medium comprising water and less than 10% v/v of an organic solvent. Preferably the reaction is carried out in presence of water, without any external organic solvent.
  • Suitable base that can be used in the process of step a) include but are not limited to: organic bases such as triethylamine, N,N-diisopropyl ethylamine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, and the like; inorganic bases such as alkali metal hydroxides selected from lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal carbonates selected from sodium carbonate, potassium carbonate, lithium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like.
  • organic bases such as triethylamine, N,N-diisopropyl ethylamine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, and the like
  • inorganic bases such as alkali metal hydroxides selected from lithium hydroxide, sodium hydroxide, potassium hydrox
  • the base may be used in its pure form or as a solution obtained by dissolving in water.
  • the base may be added to the reaction in single lot or in multiple lots or it may be added slowly and continuously over a period of time.
  • l-(2-methoxy phenoxy)-2,3-epoxy propane of Formula IV may be obtained with high purity and yield by adding base in lot- wise or slowly and continuously over a period of time.
  • the reaction may be carried out optionally in the presence of a phase transfer catalyst but preferably without using a phase transfer catalyst.
  • Suitable phase transfer catalyst includes but are not limited to tetra butyl ammonium bromide(TBAB), methyltrioctyiammonium chloride, potassium bromide, and the like. Tetra butyl ammonium bromide is preferred.
  • Suitable temperature for conducting the reaction can range from about 15°C to about 100°C, preferably at about room temperature.
  • the molar ratio of 2-methoxy phenol to l-halo-2,3 epoxy propane can range from about 1: 1.5 to about 1: 10 or preferably at about 1: 1.7 to about 1:5.
  • the reaction can be conducted till the completion of the reaction. Typically the reaction time varies from about 1 hour to about 24 hours.
  • the organic layer containing the product is separated from the reaction mixture.
  • the product present in aqueous layer may be extracted with a water immiscible solvent such as toluene and then the organic layer may be distilled to recover the residue.
  • the product obtained directly from the reaction mixture by layer separation and from distillation of organic layer may be combined and purified by suitable techniques.
  • 1- (2-methoxy phenoxy)-2,3-epoxy propane obtained as residue may be purified by using suitable techniques such as high vacuum distillation at about 120- 150 0 C.
  • l-(2-methoxyphenoxy)-2, 3-epoxypropane obtained by the process of present application is having total purity at least 95% w/w or 98% w/w or 99% w/w as determined by high performance liquid chromatography (HPLC).
  • l-(2-methoxyphenoxy)-2, 3-epoxypropane obtained by the process of present application is having less than 2.0 % w/w or less than 1.0 % w/w or less than 0.5 % w/w of one or more of dimer impurity of Formula VIII, chloro impurity of Formula IX, dihydroxy impurity of Formula X.
  • Formula VIII Formula IX Formula X
  • the residue obtained after the purification process may be used in the next step without crystallization of the residue.
  • Step b) involves reaction of 1 -(2-methoxy phenoxy)-2,3-epoxy propane of Formula IV obtained in step a) with N-(2,6-dimethylphenyl)-l-piperazine acetamide of Formula VII to form Ranolazine.
  • the reaction of step b) may be carried out without using a solvent or in a suitable solvent medium.
  • Suitable solvent that may be used in Step b) includes alcohols such as methanol, ethanol, propanol, butanol and the like; ketones such as acetone, methyl ethyl ketone methyl isobutyl ketone and the like; aliphatic hydrocarbons such as n-hexane, cyclohexane and the like; chloro hydrocarbons such as dichloromethane and the like; aromatic hydrocarbons such as toluene, xylene and the like; esters such as ethyl acetate, propyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, tert- butyl methyl ether, tetrahydrofuran and the like; water; or mixtures thereof.
  • alcohols such as methanol, ethanol, propanol, butanol and the like
  • ketones such as acetone, methyl ethyl ketone
  • the molar ratio of l-(2-methoxy phenoxy)-2,3-epoxy propane to N- (2,6-dimethylphenyl)-l-piperazine acetamide can range from about 1:0.8 to about 1: 1.5 or about 1: 1 to about 1 : 1.2.
  • Reaction may be suitably carried out at temperature ranging from about 15 0 C to about reflux temperature of the solvent used.
  • the product may be isolated by using suitable techniques such as cooling, concentrating the reaction mixture to enable complete solid separation.
  • the separated solid may be recovered by methods such as centrifugation, filtration by gravity, filtration by suction and the like.
  • the recovered solid may be further purified by recrystallization from a suitable solvent such as solvent used in the reaction of step b).
  • the wet solid may be further dried using a vacuum oven, tray dryer, air oven, fluidized bed drier and the like at about 50° C to about 80 0 C, or about 50 0 C to about 60°C. optionally under a reduced pressure for sufficient period of time.
  • Ranolazine or a salt there of obtained by the process of present application is having total purity of at least 99% w/w or at least 99.5 % w/w or at least 99.8 % w/w as determined by HPLC.
  • Ranolazine crystalline Form S obtained by the process of present application is characterized by X-ray powder diffraction (XRPD) pattern having peaks at 2 -theta values 5.0, 12.2, 13.2, 15.0, 19.8, 20.8, 25.5, and 26.5 + 0.2 degrees.
  • Ranolazine crystalline Form S obtained by the process of present application is further characterized by XRPD pattern having peaks at 2- theta values 5.0, 10.4, 12.2, 13.2, 15.0, 16.1, 19.3, 19.8, 20.8, 21.4, 23.4, 25.5, and 26.5 + 0.2 degrees.
  • Ranolazine crystalline Form S obtained by the process of present application is further characterized by XRPD pattern as shown in Fig.1.
  • Ranolazine crystalline Form S obtained by the process of present application is further characterized by having melting range from 118 0 C to about 122 0 C.
  • Ranolazine may be reacted with a pharmaceutically acceptable acid to form a salt.
  • Suitable pharmaceutically acceptable acids include hydrobromic acid, hydrochloric acid, and organic acids such as acetic acid, succinic acid, oxalic acid, tartaric acid, formic acid, and maleic acid.
  • the present patent application provides a process for the preparation of N-(2,6-dimethylphenyl)-l-piperazine acetamide of Formula VII comprises of: a) reacting 2,6-dimethylaniline Formula V with chloroacetylchloride in a solvent without any added base to get 2-chloro-N-(2,6-dimethylphenyl) acetamide of Formula VI; and
  • Suitable solvent that may be used for the reaction of step a) includes but are not limited to: water, chlorinated hydrocarbons such as dichlorome thane, chloroform, 1, 1,2-trichloroetharie and the like; aromatic hydrocarbons such as toluene, xylene and the like; ketones such as acetone, methyl ethyl ketone, methyl iso-butyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; esters such as ethyl acetate, propyl acetate, ter-butyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, ter-butyl methyl ether, t
  • the molar ratio of 2,6-dimethylaniline to chloroacetylchloride can range from about 1:0.8 to about 1:5.
  • chloroacetylchloride is added to the solution of 2,6- dimethylaniline slowly over a period of time such as for example 1 to 5 hours.
  • the reaction can be conducted till the completion of the reaction.
  • the reaction time varies from about 1 hour to about 10 hours.
  • the product obtained is recovered by conventional techniques such as centrifugation, filtration by gravity, filtration by suction and the like.
  • the recovered solid may be further purified by recrystallization from a suitable solvent such as toluene and the like.
  • 2-chloro-N-(2,6-dimethylphenyl)acetamide of Formula VI obtained by the process of present application contains less than about 2.0 % w/w or less than 1.0 % w/w or less than 0.5 % w/w of dichloro impurity of Formula XI.
  • Formula XI Step b) includes reacting 2-chloro-N-(2,6-dimethylphenyl)acetamide of
  • Suitable solvents for conducting the reaction of step b) includes alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone, methyl iso butyl ketone and the like; water; or mixtures thereof.
  • Suitable temperature for conducting the reaction may range from about 15 ° C to about 100 ° C, preferably at about reflux temperature of solvent used.
  • the molar ratio of 2-chloro-N-(2,6-dimethylphenyl)acetamide to piperazine may range from about 1 :0.8 to about 1: 10 or about 1 :2 to about 1:5.
  • reaction mixture may be cooled to room temperature or below and unwanted solids are removed by filtration.
  • the filtrate may be then quenched with water the product may be extracted in to a suitable water- immiscible solvent such as dichloromethane and the like.
  • the organic layer may be washed with sufficient amount of water to ensure that residual piperazine is not carried over in to the isolated product.
  • N-(2,6-dimethylphenyl)-l -piperazine acetamide of Formula VII obtained by the process of present application contains less than 0. 1 % w/w of residual piperazine as determined by gas chromatography(GC).
  • the solid product may be recovered by one or more of the following processes to get various crystalline forms.
  • the present patent application provides 3 novel crystalline forms of N-(2,6-dimethylphenyl)-l-piperazine acetamide of Formula VII and process for the preparation thereof.
  • the organic layer containing the product is distilled off completely under vacuum to form solid.
  • the residual dichloromethane is completely removed by co-distilling with an aliphatic or aromatic hydrocarbon solvent.
  • Suitable aliphatic hydrocarbons include n-hexane, cyclohexane, petroleum ether and the like; aromatic hydrocarbons include toluene, xylene and the like.
  • the solid product is then isolated by slurry in aliphatic or aromatic hydrocarbon solvent to get crystalline Form I of N-(2,6-dimethylphenyl)- l- piperazine acetamide.
  • XRPD X-ray powder diffraction
  • Crystalline Form I of N-(2,6-dimethylphenyl)- l-piperazine acetamide is further characterized by XRPD pattern having peaks at 2 -theta values 10.7, 12.7, 13.3, 14.6, 17.9, 19.0, 22.5, 23.2, 25.2, 26.6, 28. 1, 32.4 and 34.4 + 0.2 degrees.
  • Crystalline Form I of N-(2,6-dimethylphenyl)- l-piperazine acetamide is further characterized by XRPD pattern as shown in Fig.2.
  • Crystalline Form I of N-(2,6-dimethylphenyl)-l-piperazine acetamide is further characterized by having melting range from 1 12 °C to about 1 18 0 C.
  • the organic layer containing the product is concentrated under vacuum to a volume of not more than about 40 % of the initial volume, but solid is not separated.
  • the solid product is then isolated by adding an aliphatic or aromatic hydrocarbon solvent to the concentrated organic layer to get crystalline Form II of N-(2,6-dimethylphenyl)-l-piperazine acetamide.
  • Crystalline Form II of N-(2,6-dimethylphenyl)- l-piperazine acetamide is characterized by XRPD pattern having peaks at 2-theta values 7.2, 7.6, 10.8, 1 1.9, 17.8, 24.0 and 32.6 + 0.2 degrees.
  • Crystalline Form II of N-(2,6-dimethylphenyl)- l-piperazine acetamide is further characterized by XRPD pattern having peaks at 2-theta values 7.2, 7.6, 10.8, 1 1.9, 15.1, 17.8, 23.1, 24.0, 25.7, 32.6 and 45.4 + 0.2 degrees.
  • Crystalline Form II of N-(2,6-dimethylphenyl)- l-piperazine acetamide is further characterized by XRPD pattern as shown in Fig.3.
  • Crystalline Form II of N-(2,6-dimetbylphenyl)- l-piperazine acetamide is further characterized by having melting range from 1 14 0 C to about 150 0 C.
  • the organic layer containing the product may be treated with an aqueous acid to extract the product into aqueous layer; and then treating the aqueous layer with a base followed by extracting product with a solvent such as dichloromethane and the like.
  • a solvent such as dichloromethane and the like.
  • the organic layer is distilled off completely under vacuum to form solid.
  • the residual dichloromethane is completely removed by co-distilling with an aliphatic or aromatic hydrocarbon solvent.
  • the solid product is then isolated by slurry in aliphatic or aromatic hydrocarbon solvent to get crystalline Form III of N-(2,6-dimethylphenyl)-l- piperazine acetamide.
  • Crystalline Form III of N-(2,6-dimethyiphenyl)-l-piperazine acetamide is characterized by XRPD pattern having peaks at 2-theta values 6.3, 9.1, 11.4, 16.7, 20.7, 23.5 and 28.8 + 0.2 degrees.
  • Crystalline Form III of N-(2,6-dimethylphenyl)-l-piperazine acetamide is further characterized by XRPD pattern having peaks at 2-theta values 6.4, 9.1, 11.4, 16.7, 17.3, 19.5, 20.7, 23.5, 27.7, 28.8, 30.7 and 33.3 + 0.2 degrees.
  • Crystalline Form III of N-(2,6-dimethylphenyl)- l-piperazine acetamide is further characterized by XRPD pattern as shown in Fig.4.
  • Crystalline Form III of N-(2,6-dimethylphenyl)-l-piperazine acetamide is further characterized by having melting range from 150 0 C to about 170 0 C.
  • N-(2,6-dimethylphenyl)-l-piperazine acetamide crystalline forms I, II and III obtained by the process of present application contains less than about 1.0 % w/w or less than 0.5 % w/w or less than 0.2 % w/w one or more of dimer impurity of Formula XII, dipiperazine impurity of Formula XIII.
  • the present patent application also relates to use of l-(2-methoxy phenoxy)-2,3-epoxy propane and N-(2,6-dimethylphenyl)-l-piperazine acetamide obtained by the process of present application in the synthesis of active pharmaceutical ingredients including Ranolazine.
  • the process of the present invention involves the usage of inexpensive, non-hazardous and easily available raw materials for making the process suitable for commercial manufacturing.
  • Example 1 Preparation of l-(2-methoxy phenoxy)-2,3-epoxy propane 200 ml of caustic lye (48 % aqueous sodium hydroxide) was charged into a flask containing 2.6 L of water under stirring at room temperature. 400 gm of 2-methoxyphenol was added to the solution and maintained for 30 minutes at room temperature. 400 gm of l-chloro-2,3 epoxy propane was added slowly to the reaction mixture and maintained for 15-18 hours at room temperature. After completion of the reaction as monitored by TLC, the reaction mixture was allowed to settle and the lower organic layer containing product was separated. The aqueous layer was extracted with 600 ml of toluene.
  • the toluene layer was washed with water and 200 ml of saturated NaCl solution.
  • the toluene layer distilled under vacuum to get 475 gm of overall residue.
  • the product obtained was purified by distillation under high vacuum at about 130- 150 0 C to get 367 gm of the title compound. Purity by HPLC: 98.8% w/w
  • Example 2 Preparation of l-(2-methoxy phenoxy)-2,3-epoxy propane by slow addition of base. 50 gm of 2-methoxy phenol, 65 gm of epichlorohj ⁇ drin, 10 gm of TBAB were charged in flask containing 300 ml of water and reaction mixture was cooled to 0- 15 0 C. A solution of NaOH (25 gm dissolved in 25 ml of water) was added slowly to the reaction mixture for about 2 hours. After addition completed, the reaction mixture was maintained for about 16 hours at room temperature. After completion of the reaction (monitored by TLC), the lower organic layer containing product was separated. The aqueous layer was extracted with toluene (250 ml).
  • the organic layer containing the product was combined with toluene layer and washed with water (100 ml), 5 % aqueous sodium hydroxide solution (100 ml) and finally with 10% aqueous sodium chloride solution(100 ml).
  • the solvent was distilled off completely under vacuum to get the title compound as oil (66 gm) .
  • the above obtained oily product was subjected to high vacuum distillation at about 130-150 0 C to get 48 gm of pure title compound.
  • the organic layer containing the product was combined with toluene layer and washed with water (100 ml), 5 % aqueous sodium hydroxide solution (100 ml) and finally with 10% aqueous sodium chloride solution( 100 ml).
  • the solvent was distilled off completely under vacuum to get the title compound as oil (70 gm).
  • the above obtained oily product was subjected to high vacuum distillation at about 130-150 0 C to get 50 gm of pure title compound.
  • Example 4 Preparation of l-(2-methoxy phenoxy)-2,3-epoxy propane by slow addition of base and without TBAB.
  • the organic layer containing the product was combined with toluene layer and washed with water (100 ml), 5 % aqueous sodium hydroxide solution (100 ml) and finally with 10% aqueous sodium chloride solution(100 ml) .
  • the solvent was distilled off completely under vacuum to get the title compound as oil (67 gm).
  • the above obtained oily product was subjected to high vacuum distillation at about 130- 150 0 C to get 58 gm of pure title compound.
  • Example 7 Purification of 2-chloro-N-(2,6-dimethylphenyl) acetamide 42 gm of 2-chloro-N-(2,6-dimethylphenyl) acetamide (dichloro impurity content 1.0% w/w) was charged in a flask containing 125 ml of toluene and heated to 85-95°C. The reaction mixture was stirred for about 30 minutes. The reaction mixture was then cooled to 10 0 C and was maintained for about 30 minutes. The solid product was filtered, washed with toluene (10 ml) and dried to give 35 gm of the title compound
  • Example 10 Preparation of N -(2, 6 -dime thylphenyl)- l -piperazine acetamide crystalline Form III 10 gm of N-(2,6-dimethylphenyl)- l-piperazine acetamide (having purity by HPLC 98.28% w/w) was dissolved in 60 ml of dichloromethane and 60 ml of water at 25-35°C. The reaction mixture pH was adjusted to about 2 using 32% aqueous HCl (6 ml) and stirred for 10 minutes. The aqueous layer was separated and pH was adjusted to about 10.5 using aqueous ammonia solution (25 ml).
  • N-(2,6-dimethylphenyl)-l-piperazine acetamide (20 gm), l-(2-methoxy phenoxy)-2,3-epoxy propane (16 gm) and methanol (150 ml) were charged in a flask and heated to reflux.
  • the reaction mixture was stirred at reflux for about 5 hours and carbon treatment given to methanol layer. Taken methanol layer and distilled off completely under vacuum. 48 ml of methanol was added to the residue and stirred at 25-30°C for about 1-2 hours.
  • the reaction mixture was cooled to about 0-5°C and stirred for about 1 hour.
  • the solid was filtered and washed with methanol (6 ml) .
  • the wet solid was dried at 50-60 0 C to get 28 gm of the title compound. Purity by HPLC: 99.89 % w/w

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Abstract

La présente invention concerne un procédé amélioré de préparation de la Ranolazine, ses sels pharmaceutiquement acceptables et des intermédiaires de ceux-ci. L'invention concerne spécifiquement des procédés de préparation du 1-(2-méthoxy phénoxy)-2,3-époxypropane dans un milieu de solvants essentiellement aqueux et du 2-chloro-N-(2,6-diméthylphényl)acétamide sans utiliser de base additionnelle, qui sont des intermédiaires, utiles dans la préparation de la Ranolazine et des sels pharmaceutiquement acceptables de celle-ci.
PCT/IN2009/000463 2008-08-28 2009-08-21 Préparation de la ranolazine, ses sels et des intermédiaires de ceux-ci WO2010023687A2 (fr)

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CN101838249A (zh) * 2010-03-19 2010-09-22 浙江华海药业股份有限公司 一种制备高纯度愈创木酚缩水甘油醚的方法
WO2010136522A2 (fr) * 2009-05-27 2010-12-02 Medichem S.A. Dérivé de pipérazine exempt, ou sensiblement exempt, d'une génotoxicité potentielle, et procédé de préparation associé
WO2011160396A1 (fr) 2010-06-25 2011-12-29 上海冠杰生物医药科技有限公司 Procédé pour la préparation de ranolazine
CN103570645A (zh) * 2012-08-01 2014-02-12 上海迪赛诺化学制药有限公司 一种制备n-(2,6-二甲基苯基)-2-(1-哌嗪基)乙酰胺的方法

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WO2010136522A2 (fr) * 2009-05-27 2010-12-02 Medichem S.A. Dérivé de pipérazine exempt, ou sensiblement exempt, d'une génotoxicité potentielle, et procédé de préparation associé
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CN101838249A (zh) * 2010-03-19 2010-09-22 浙江华海药业股份有限公司 一种制备高纯度愈创木酚缩水甘油醚的方法
CN101838249B (zh) * 2010-03-19 2015-08-19 浙江华海药业股份有限公司 一种制备高纯度愈创木酚缩水甘油醚的方法
WO2011160396A1 (fr) 2010-06-25 2011-12-29 上海冠杰生物医药科技有限公司 Procédé pour la préparation de ranolazine
CN103570645A (zh) * 2012-08-01 2014-02-12 上海迪赛诺化学制药有限公司 一种制备n-(2,6-二甲基苯基)-2-(1-哌嗪基)乙酰胺的方法

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