WO2010097805A1 - Procédé pour la préparation de ranolazine - Google Patents

Procédé pour la préparation de ranolazine Download PDF

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Publication number
WO2010097805A1
WO2010097805A1 PCT/IN2010/000090 IN2010000090W WO2010097805A1 WO 2010097805 A1 WO2010097805 A1 WO 2010097805A1 IN 2010000090 W IN2010000090 W IN 2010000090W WO 2010097805 A1 WO2010097805 A1 WO 2010097805A1
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WO
WIPO (PCT)
Prior art keywords
ranolazine
solvent
acetone
mixture
methyl
Prior art date
Application number
PCT/IN2010/000090
Other languages
English (en)
Inventor
Rajinder Singh Siyan
Sunilkumar Vinubhai Gohel
Raju Walunj
Smart Anurag
Girij Pal Singh
Original Assignee
Lupin Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lupin Limited filed Critical Lupin Limited
Publication of WO2010097805A1 publication Critical patent/WO2010097805A1/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 invention relates to novel processes for the preparation of ranolazine (I) to yield ranolazine with high purity.
  • 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.
  • 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
  • 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.
  • 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.
  • the present invention is related to a novel process for the preparation of ranolazine (I), having purity > 99.8% that comprises the following steps:
  • 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.
  • 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: '
  • 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.
  • step 1 of the present invention can be carried out in water miscible organic solvent that include tetrahydrofuran, 1,4-dioxane, dimethylforarnide, N-methy ⁇ -pyrrolidone, acetonitrile, propionitrile, acetone, ethylmethyl ketone and mixtures thereof.
  • the most preferred solvent is acetone.
  • step 2 comprises of reaction of chloroacetamide (VII) with piperazine to give piperazine acetamide (II).
  • 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.
  • 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 t
  • step 3 comprises of reaction of piperazine acetamide (II) with epoxide compound (III) to give ranolazine in the presence of organic solvent.
  • 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.
  • aromatic hydrocarbons like benzene, toluene and xylene
  • esters like ethyl acetate and isopropyl acetate
  • ethers such as ethyl ether, methyl t-but
  • 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.
  • 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.
  • ranolazine free base (I) obtained by the process of the present invention is > 99.8%.
  • 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.
  • 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,
  • ranolazine free base lies in the range of 119- ⁇ 21°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
  • 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,
  • 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)
  • 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 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%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré et nouveau pour la préparation de ranolazine.
PCT/IN2010/000090 2009-02-24 2010-02-17 Procédé pour la préparation de ranolazine WO2010097805A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN349/KOL/2009 2009-02-24
IN349KO2009 2009-02-24

Publications (1)

Publication Number Publication Date
WO2010097805A1 true WO2010097805A1 (fr) 2010-09-02

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102070483A (zh) * 2010-12-03 2011-05-25 蚌埠丰原医药科技发展有限公司 一种制备利多卡因的方法
CN102070484A (zh) * 2010-12-22 2011-05-25 蚌埠丰原医药科技发展有限公司 一种制备丙胺卡因或其盐酸盐的方法
CN102093248A (zh) * 2010-12-22 2011-06-15 蚌埠丰原医药科技发展有限公司 一种制备盐酸丙胺卡因的方法
CN104529812A (zh) * 2014-12-31 2015-04-22 济南诚汇双达化工有限公司 一种盐酸丙胺卡因的制备方法
WO2016142819A2 (fr) 2015-03-10 2016-09-15 Unichem Laboratories Limited Nouveau procédé de préparation de ranolazine
CN109456285A (zh) * 2018-10-29 2019-03-12 安徽省庆云医药股份有限公司 一种雷诺嗪的制备方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4567264A (en) 1983-05-18 1986-01-28 Syntex (U.S.A.) Inc. Cardioselective aryloxy- and arylthio- hydroxypropylene-piperazinyl acetanilides which affect calcium entry
EP0483932A1 (fr) 1990-10-31 1992-05-06 Richter Gedeon Vegyeszeti Gyar R.T. Procédé pour la préparation de dérivés de la pipérazine
WO2006008753A1 (fr) * 2004-07-19 2006-01-26 Unichem Laboratories Limited Forme cristalline et amorphe de ranolazine et son processus de fabrication
WO2008047388A2 (fr) 2006-10-20 2008-04-24 Ind-Swift Laboratories Limited Procédé amélioré de préparation de ranolazine
WO2008139492A2 (fr) 2007-05-15 2008-11-20 Natco Pharma Limited Procédé de préparation de base de ranolazine de haute pureté
WO2009153691A2 (fr) * 2008-06-20 2009-12-23 Kimberly-Clark Worldwide, Inc. Procédé permettant de limiter la corrosion d’un capteur dans des articles absorbants
WO2010025370A2 (fr) * 2008-08-28 2010-03-04 Dr. Reddy's Laboratories Ltd. Préparation de ranolazine

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4567264A (en) 1983-05-18 1986-01-28 Syntex (U.S.A.) Inc. Cardioselective aryloxy- and arylthio- hydroxypropylene-piperazinyl acetanilides which affect calcium entry
EP0483932A1 (fr) 1990-10-31 1992-05-06 Richter Gedeon Vegyeszeti Gyar R.T. Procédé pour la préparation de dérivés de la pipérazine
WO2006008753A1 (fr) * 2004-07-19 2006-01-26 Unichem Laboratories Limited Forme cristalline et amorphe de ranolazine et son processus de fabrication
WO2008047388A2 (fr) 2006-10-20 2008-04-24 Ind-Swift Laboratories Limited Procédé amélioré de préparation de ranolazine
WO2008139492A2 (fr) 2007-05-15 2008-11-20 Natco Pharma Limited Procédé de préparation de base de ranolazine de haute pureté
WO2009153691A2 (fr) * 2008-06-20 2009-12-23 Kimberly-Clark Worldwide, Inc. Procédé permettant de limiter la corrosion d’un capteur dans des articles absorbants
WO2010025370A2 (fr) * 2008-08-28 2010-03-04 Dr. Reddy's Laboratories Ltd. Préparation de ranolazine

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102070483A (zh) * 2010-12-03 2011-05-25 蚌埠丰原医药科技发展有限公司 一种制备利多卡因的方法
CN102070484A (zh) * 2010-12-22 2011-05-25 蚌埠丰原医药科技发展有限公司 一种制备丙胺卡因或其盐酸盐的方法
CN102093248A (zh) * 2010-12-22 2011-06-15 蚌埠丰原医药科技发展有限公司 一种制备盐酸丙胺卡因的方法
CN104529812A (zh) * 2014-12-31 2015-04-22 济南诚汇双达化工有限公司 一种盐酸丙胺卡因的制备方法
WO2016142819A2 (fr) 2015-03-10 2016-09-15 Unichem Laboratories Limited Nouveau procédé de préparation de ranolazine
WO2016142819A3 (fr) * 2015-03-10 2016-10-27 Unichem Laboratories Limited Nouveau procédé de préparation de ranolazine
EP3782992A1 (fr) 2015-03-10 2021-02-24 Unichem Laboratories Limited Nouveau procédé de préparation de ranolazine
CN109456285A (zh) * 2018-10-29 2019-03-12 安徽省庆云医药股份有限公司 一种雷诺嗪的制备方法

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