WO2006090265A2 - Procedes de preparation de levetiracetam, son intermediaire et utilisation de levetiracetam dans des compositions pharmaceutiques - Google Patents

Procedes de preparation de levetiracetam, son intermediaire et utilisation de levetiracetam dans des compositions pharmaceutiques Download PDF

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Publication number
WO2006090265A2
WO2006090265A2 PCT/IB2006/000424 IB2006000424W WO2006090265A2 WO 2006090265 A2 WO2006090265 A2 WO 2006090265A2 IB 2006000424 W IB2006000424 W IB 2006000424W WO 2006090265 A2 WO2006090265 A2 WO 2006090265A2
Authority
WO
WIPO (PCT)
Prior art keywords
ammonium
formula
levetiracetam
reaction mixture
aminobutanamide
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2006/000424
Other languages
English (en)
Other versions
WO2006090265A3 (fr
Inventor
Surender Kumar Dhingra
Surinder Kumar Arora
Kaptan Singh
Mohan Prasad
Yatendra Kumar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
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 Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of WO2006090265A2 publication Critical patent/WO2006090265A2/fr
Publication of WO2006090265A3 publication Critical patent/WO2006090265A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom

Definitions

  • the field of the invention relates to processes for the preparation of (S)-2- aminobutanamide of Formula I, and to the use of the compound of Formula I as intermediate for the preparation of levetiracetam of Formula II.
  • the invention also relates to a process for the preparation of levetiracetam and pharmaceutical compositions that include the levetiracetam.
  • Levetiracetam is an antiepileptic drug indicated as adjunctive therapy in the treatment of partial onset seizures in adults with epilepsy.
  • Levetiracetam is a single enantiomer and the chemical name for levetiracetam is (S)- ⁇ -ethyl-2-oxo-l- pyrrolidineacetamide.
  • Schemes Several processes have been reported for the preparation of (S)-2- aminobutanamide and levetiracetam.
  • 1,309,692 discloses the compound ⁇ -ethyl-2-oxo-l-pyrrolidineacetamide (melting point 112 0 C) and states that the compounds of this type can be used for therapeutic purposes, for example for the treatment of motion sickness, hyperkinesia, hypertonia and epilepsy.
  • U.S. Patent No. 4,969,943 discloses the levorotatory isomer of ce-ethyl-2-oxo-l- pyrrolidineacetamide, which has the absolute S configuration.
  • the patent discloses the preparation of levetiracetam by reacting (S)- ⁇ -ethyl-2-oxopyrrolidineacetic acid successively with alkylhaloformate and with ammonia. It also discloses the preparation of levitiracetam by cyclizing an (S)-2-aminobutanamide.
  • U.S. Patent Publication Nos. 2004/0192757 and 2004/0092576 disclose a process for the preparation of levetiracetam from corresponding unsaturated 2-oxo-l -pyrrolidine . derivative by asymmetric hydrogenation using a chiral catalyst.
  • U.S. Patent Publication No. 2004/0204476 discloses a method of preparing levetiracetam by ammonolysis.
  • U.S. Patent No. 6,124,473 and U.S. Patent Publication No. 2004/0204476 disclose the methods of separating optical isomers of levetiracetam by chromatographic techniques.
  • Journal of American Chemical Society, 1955, 77, 1522 discloses the preparation of amino acid amides by contacting the corresponding freebase with ammonia at 0 0 C and keeping for three days.
  • the present inventors have observed that the methods known in the art require the maintenance at low temperature for considerable number of days which leads to the formation of large quantity of byproducts and impurities including dimeric impurity. Further, the levetiracetam gets racemized due to the alkaline conditions of the reaction mixture during the cyclization step.
  • the process includes: a) reacting a compound of Formula III,
  • R represents C 1 -Cs alkyl, haloalkyl, aryl, arylalkyl or heteroaryl , or an acid addition salt thereof, with ammonia in the presence of an ammonium salt; and b) isolating the (S)-2-aminobutanamide of Formula I.
  • the process may include further drying of the product obtained.
  • the process may include further converting the product obtained into levetiracetam.
  • the levetiracetam may be made into a finished dosage form with one or more pharmaceutically acceptable excipients.
  • the process may produce the levetiracetam having optical purity more than 99.5%. In particular, it may produce the levetiracetam having optical purity more than 99.8%.
  • the process includes: a) reacting a compound of Formula III,
  • the process includes: a) reacting a compound of Formula III,
  • the process may include further drying of the product obtained.
  • the process may produce the levetiracetam having optical purity more than 99.5%. In particular, it may produce the levetiracetam having optical purity more than 99.8%.
  • a pharmaceutical composition that includes a therapeutically effective amount of levetiracetam having optical purity more than 99.5%; and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the (S)-2-aminobutanamide can be prepared by an ammonolysis of (S) ⁇ 2-aminobutyric acid ester, and the reaction can be carried out at room temperature.
  • the inventors have found that the use of ammonium salts along with ammonia gas helps in reducing the reaction time and also retards the impurity formation.
  • the inventors have also found that undesired racemization of the levetiracetam can be avoided if pH of the reaction mixture is adjusted before isolating the levetiracetam. The process also enables the production of crude levetiracetam having a high chemical purity.
  • the inventors have developed a process for the preparation of (S)-2- aminobutanamide of Formula I.
  • the process involves reacting (S)-2-aminobutanoic acid ester of Formula III,
  • R represents C 1 -Cs alkyl, haloalkyl, aryl, arylalkyl or heteroaryl , or an acid addition salt thereof, with ammonia in the presence of an ammonium salt.
  • the (S)-2-aminobutanoic acid ester of Formula III may be dissolved in a solvent and ammonia gas may be passed through the reaction mixture at a temperature less than about O 0 C, followed by the addition of an ammonium salt. The temperature may be raised and maintained between about 10° to 6O 0 C until the completion of the reaction.
  • solvent includes any solvent or solvent mixture in which (S)-2- aminobutanoic acid ester is soluble, including, for example primary alcohols.
  • ammonium salts include ammonium sulfate, ammonium chloride, ammonium formate, ammonium acetate, ammonium propionate, ammonium persulfate, ammonium sulfide, ammonium phosphate, ammonium nitrite, ammonium nitrate, ammonium carbonate, ammonium bicarbonate, ammonium chlorate, ammonium bromide, ammonium iodide and ammonium fluoride.
  • the product may be isolated from the reaction mixture by a technique which includes, for example, distillation, distillation under vacuum, filtration, filtration under vacuum, evaporation, decantation, and centrifugation.
  • the product thus isolated may be further purified or additionally purified, by employing commonly practiced recrystallization techniques using solvent/antisolvent mixture to obtain pure (S)-2-aminobutanamide.
  • the inventors also have developed a process for the preparation of levetiracetam by reacting (S)-2-aminobutanamide of Formula I with 4-chlorobutyryl chloride to get (S)- N-[l-(aminocarbony)propyl]-4-chlorobutyramide; cyclizing the (S)-N-[I- (aminocarbony)propyl]-4-chlorobutyramide in the presence of an alkali; adjusting pH of the reaction mixture; and isolating the levetiracetam from the reaction mass.
  • (S)-2-aminobutanamide may be reacted with 4-chlorobutyryl chloride in the presence of an organic solvent to get (S)-N-[l-(aminocarbony)propyl]-4- chlorobutyramide, which may be further cyclized in the presence of an alkali.
  • the organic solvent and alkali which can be used in the reaction are known to a person of ordinary skill in the art. Any organic solvents can be used which are inert and do not change under the reaction conditions. Examples of alkali include salts of lithium, sodium, or potassium.
  • the pH of the reaction mixture may be adjusted in the range from about 7 to about 8.5 before isolating the levetiracetam.
  • the levetiracetam may be isolated from the reaction mixture by a technique which includes, for example, distillation, distillation under vacuum, filtration, filtration under vacuum, evaporation, decantation, and centrifugation.
  • the levetiracetam thus isolated may be farther purified or additionally purified, by employing commonly practiced recrystallization techniques using solvent/antisolvent mixture to obtain pure levetiracetam.
  • Methyl (S)-2-aminobutyric acid ester (220 g) was dissolved in methanol (1200 ml). The reaction mixture was cooled to -5° to - 10 0 C and ammonia gas was passed for about 4 hours. The temperature was slowly raised to 20 0 C in about 2 to 3 hours and ammonium sulfate (120 g) was added at 20° to 25°C. The reaction mixture was stirred at 20° to 25°C for 2 to 3 days. The reaction mixture was filtered through celite bed and washed with methanol (100 ml). The combined filtrate was concentrated to get crude product, which was recrystallized from methanol-ethyl acetate to get the title compound.
  • Acetonitrile (1800 ml) and (S)-2-aminobutyramide (100 g) were mixed at about 25 0 C and stirred under nitrogen atmosphere.
  • Pulverized potassium carbonate (203 g) was added to the reaction mixture and cooled to -5 0 C.
  • a solution of 4-chlorobutyryl chloride (138.25 g) in acetonitrile (100 ml) was added slowly to the reaction mixture at a temperature of -5 0 C to O 0 C for about 60 minutes. The reaction mixture was stirred at the same temperature until the completion of the reaction.
  • the mixture was filtered through celite bed and washed with acetonitrile (200 ml).
  • the pH of the resultant mixture was adjusted to the range of 7.5 to 8.0 with acetic acid (31 g) and stirred for 15 minutes.
  • the temperature of the reaction mixture was raised to 2O 0 C and stirred for 15 minutes at 20° to 25 0 C.
  • the reaction mixture was filtered through celite bed, washed with methylene chloride (300 ml), and concentrated under vacuum at 40° to 45 0 C.
  • Toluene (100 ml) was added to the residue and recovered under vacuum at 40° to 45 0 C.
  • Ethyl acetate (300 ml) was added to the residue, cooled slowly to 10° to 15° C, stirred for 3 hours, filtered and washed.
  • the product obtained was dried under vacuum at 40° to 45 0 C for 16 hours to obtain the title compound.

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

Abstract

L'invention concerne des procédés permettant de préparer (S)-2-aminobutanamide de la formule I ainsi que l'utilisation du composé de la formule I comme intermédiaire pour la préparation de lévétiracétam de formule II. L'invention concerne également un procédé de préparation de lévétiracétam et des compositions pharmaceutiques comportant le lévétiracétam.
PCT/IB2006/000424 2005-02-28 2006-02-28 Procedes de preparation de levetiracetam, son intermediaire et utilisation de levetiracetam dans des compositions pharmaceutiques Ceased WO2006090265A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN435DE2005 2005-02-28
IN435/DEL/2005 2005-02-28

Publications (2)

Publication Number Publication Date
WO2006090265A2 true WO2006090265A2 (fr) 2006-08-31
WO2006090265A3 WO2006090265A3 (fr) 2006-10-19

Family

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PCT/IB2006/000424 Ceased WO2006090265A2 (fr) 2005-02-28 2006-02-28 Procedes de preparation de levetiracetam, son intermediaire et utilisation de levetiracetam dans des compositions pharmaceutiques

Country Status (1)

Country Link
WO (1) WO2006090265A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008077035A3 (fr) * 2006-12-18 2008-10-09 Reddys Lab Ltd Dr Procédés de préparation de lévétiracétam
CN102558012A (zh) * 2012-03-15 2012-07-11 台州市知青化工有限公司 一种左乙拉西坦的合成方法
CN102898324A (zh) * 2012-10-19 2013-01-30 阜新龙瑞化工有限责任公司 一种(s)-2-氨基丁酰胺盐酸盐的制备方法
CN114763334A (zh) * 2021-01-14 2022-07-19 浙江华海药业股份有限公司 一种左乙拉西坦3-位异构体杂质及其制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8412357D0 (en) * 1984-05-15 1984-06-20 Ucb Sa Pharmaceutical composition
CA2515090A1 (fr) * 2003-02-03 2004-08-19 Teva Pharmaceutical Industries Ltd Procede de production de levetiracetam
US7531673B2 (en) * 2004-02-18 2009-05-12 Dr. Reddy's Laboratories Limited Preparation of amino acid amides

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008077035A3 (fr) * 2006-12-18 2008-10-09 Reddys Lab Ltd Dr Procédés de préparation de lévétiracétam
CN102558012A (zh) * 2012-03-15 2012-07-11 台州市知青化工有限公司 一种左乙拉西坦的合成方法
CN102558012B (zh) * 2012-03-15 2013-12-25 台州市知青化工有限公司 一种左乙拉西坦的合成方法
CN102898324A (zh) * 2012-10-19 2013-01-30 阜新龙瑞化工有限责任公司 一种(s)-2-氨基丁酰胺盐酸盐的制备方法
CN114763334A (zh) * 2021-01-14 2022-07-19 浙江华海药业股份有限公司 一种左乙拉西坦3-位异构体杂质及其制备方法

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