WO2006127300A1 - SYNTHÈSE DU (S)-α-ÉTHYL-2-OXO-1-PYRROLIDINEACÉTAMIDE - Google Patents

SYNTHÈSE DU (S)-α-ÉTHYL-2-OXO-1-PYRROLIDINEACÉTAMIDE Download PDF

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Publication number
WO2006127300A1
WO2006127300A1 PCT/US2006/018462 US2006018462W WO2006127300A1 WO 2006127300 A1 WO2006127300 A1 WO 2006127300A1 US 2006018462 W US2006018462 W US 2006018462W WO 2006127300 A1 WO2006127300 A1 WO 2006127300A1
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WO
WIPO (PCT)
Prior art keywords
ethyl
oxo
temperature
pyrrolidineacetamide
solids
Prior art date
Application number
PCT/US2006/018462
Other languages
English (en)
Inventor
Gianluigi Rizzuti
Edoardo Gianolli
Original Assignee
Cambrex Charles City, Inc.
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 Cambrex Charles City, Inc. filed Critical Cambrex Charles City, Inc.
Publication of WO2006127300A1 publication Critical patent/WO2006127300A1/fr

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Classifications

    • 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

  • This invention broadly relates to a method for synthesizing (S)- ⁇ -ethyl-
  • Levetiracetam (sold under the tradename Keppra®), possess antiepileptic activity and finds use in connection with the treatment of partial onset seizures in adults with epilepsy.
  • racemic composition ⁇ - ethyl-2-oxo-l -pyrrolidineamide was first described in G.B. 1,309,692 and in addition to epilepsy was thought to be useful for the treatment of motion sickness, hyperkinesias and hypertonia.
  • the optically pure levorotatory isomer is described in U.S. 4,696,943 as being useful for the treatment and prevention of hypoxia and ischemic type aggressions of the central nervous system, such as the treatment of (1) the consequences of cerebral vascular accidents and of cranial traumas, (2) the consequences of the ageing process, or (3) circulatory insufficiencies of the central nervous system resulting from cerebral-ischemic or hypoxic accidents occurring for example during birth.
  • This patent also suggests that the compound may be used in the treatment of hypoxic-type diseases of other organs or tissues, such as the heart and the kidneys.
  • X is ZOOC — and Y is a methylene
  • tetrabutylammonium bromide when the compound is a halide
  • alkyl haloformate (hereinafter also referred to as levo acid) is reacted successively with (1) an alkyl haloformate of the formula HaICOOZ in which Hal represents a halogen atom and Z an alkyl radical having 1 to 4 carbon atoms and with (2) ammonia.
  • the alkyl haloformate is preferably ethyl chloroformate and the reaction is generally carried out in dichloromethane at a very low temperature between -10 and - 6O 0 C.
  • levetiracetam constitutes an important therapeutic agent, additional and improved ways of preparing it are of value to the pharmaceutical arts.
  • the present invention is directed to an improved method of producing
  • the present invention relates to a method in which (S)- ⁇ - ethyl-2-oxo-l-pyrrolidineacetic acid (levo acid) is contacted with di-tert-butyl dicarbonate, ammonium bicarbonate and pyridine in acetonitrile to yield levetiracetam.
  • the present invention pertains to a method for purifying a crude acetonitrile solution of levetiracetam in which the solution first is concentrated and mixed with ethyl acetate to cause formation of crude levetiracetam solids. The slurry then is cooled; the levetiracetam solids are filtered, washed with cold ethyl acetate and then dried. The crude levetiracetam solids are dissolved in a hot aqueous acetone solution and then recrystallized, washed with cold acetone and dried to produce the pure levetiracetam product.
  • levo acid is contacted with di-tert-butyl dicarbonate, ammonium bicarbonate and pyridine in an inert solvent, e.g., acetonitrile to yield levetiracetam.
  • an inert solvent e.g., acetonitrile
  • Acetone can also be used but it tends to reduce the rate of reaction.
  • the reaction is preferably conducted at atmospheric pressure under an inert atmosphere, e.g., nitrogen, at a mild temperature in the range of 10-20 0 C.
  • the levo acid ((S)- ⁇ -ethyl-2-oxo-l-pyrrolidineacetic acid) used in this reaction can be obtained from the racemic ⁇ -ethyl-2-oxo-l-pyrrolidineacetic acid by chemical resolution in accordance with known methods, for example, by forming a salt of this acid with an optically active base and isolating the salt formed with the isomer, (S)- ⁇ -2-oxo-l-pyrrolidineacetic acid, by successive crystallizations in an appropriate solvent (for example benzene).
  • an appropriate solvent for example benzene
  • Optically active bases which can be used for this resolution include alkaloids such as brucine, quinine, strychnine, quinidine and cinchonidine and amines such as ⁇ -methylbenzylamine and dehydroabietylamine.
  • alkaloids such as brucine, quinine, strychnine, quinidine and cinchonidine
  • amines such as ⁇ -methylbenzylamine and dehydroabietylamine.
  • racemic ⁇ -ethyl-2-oxo-l-pyrrolidineacetic acid used as the starting material for the resolution can be obtained by saponifying a corresponding alkyl ester, the synthesis of which has been described previously in the earlier mentioned G.B. Pat. 1,309,692 (also incorporated herein by reference).
  • Other ways of obtaining the levo acid also can be used and the present invention is not to be limited to any particular way for its preparation.
  • the levo acid is slurried in an inert solvent, preferably acetonitrile under an inert atmosphere, e.g., nitrogen, at a mild temperature of about 10-15 0 C to establish a concentration of about 10 to 20 g/ml. Then, the levo acid is treated with about a 5 to 20% molar excess of di-tert- butyl dicarbonate (DiBOC).
  • DiBOC di-tert- butyl dicarbonate
  • the level of excess DiBOC is an economic consideration but does not affect the yield of quality of the product. As understood by those skilled in the art, water needs to be excluded from the equipment and reagents as DiBOC is very moisture sensitive.
  • Ammonium bicarbonate in about a 10 to 40% molar excess also is added with mixing to the levo acid slurry.
  • pyridine in an amount of about 50 mole % of the ammonium bicarbonate is added and mixing is continued. The addition of the ammonium bicarbonate must precede the addition of the pyridine. Otherwise, uncontrolled gas generation will occur.
  • reaction temperature not exceed about 20 0 C; higher temperatures contribute to racemization and formation of the undesired (R)-isomer.
  • the solution is heated to a temperature of about 25-30 0 C and then the reaction mixture is filtered to remove un-dissolved solids.
  • the solids can be washed with acetonitrile and the wash liquid collected and mixed with the filtrate from the initial filtration. The washed solids are discarded.
  • the process of the present invention provides for the conversion of levo acid to levetiracetam at a very mild temperature (about 10-20 0 C) instead of the very low temperatures required by the prior art (-60 to -10 0 C).
  • the process of the present invention also avoids the use of hazardous reagents, such as ammonia, instead replacing ammonia with an easy to handle ammonium salt.
  • the combined filtrate and wash is then subjected to a vacuum distillation, with mild heating. It may be necessary to heat the solution to a temperature of about 25-40 0 C during the distillation. With the vacuum distillation, the solution is concentrated, preferably to less than about 20% of its original volume. The distillate is discarded. As the solution becomes more concentrated, solids will begin to precipitate from the solution. Once one obtains about an 80% reduction in volume, ethyl acetate (EA) is added to the slurry.
  • EA ethyl acetate
  • An additional amount of ethyl acetate is added to the slurry and the mixture is heated to a temperature of about 70-80 0 C to dissolve solids. Once the solids have dissolved, the solution is cooled to a temperature of about 30-45 0 C and held at that temperature for 30 minutes to an hour. Over the next 30 minutes to an hour the mixture then is cooled further to a temperature of about 0-10 0 C and then is again held at that temperature for an additional 30 minutes to an hour.
  • the slurry which results from the controlled cooling is filtered and the recovered solids are washed with cold ethyl acetate. The filtrate and wash liquids are both discarded. The recovered solids are dried under a vacuum ( ⁇ 20 in. Hg) for a time period of 8 to 12 hours and at a temperature of about 60-70 0 C. These solids constitute a crude levetiracetam product.
  • the solids are mixed with sufficient water and acetone to produce a mixture containing about 18% solids by weight per liquid volume.
  • the aqueous acetone solution preferably contains about 1% water (by volume).
  • the initial slurry so-formed then is heated to a temperature of about 50-55 0 C to dissolve the solids.
  • both the amount of water in the acetone and the quantity of aqueous acetone used to prepare the initial solution are important.
  • the level of water in the acetone increases the ultimate yield of levetiracetam recovered suffers.
  • the level of residual impurities in the product is not acceptable.
  • An aqueous concentration of between 0.5 and 2.0 % by volume is preferred.
  • the aqueous acetone is used in an amount (volume) about 5 to 7 times the weight of the product. Lower amounts adversely impacts the purity of the product, while higher amounts are economically disadvantageous.
  • aqueous acetone solution is passed though a filter provided with a filter aid, such as a diatomaceous earth (Celatom®) to remove any undissolved solids.
  • a filter aid such as a diatomaceous earth (Celatom®) to remove any undissolved solids.
  • the filter cake is washed with another portion of the 1% water/acetone solution and the wash liquid is combined with the original filtrate. The filter cake is discarded.
  • the combined filtrate and wash liquid is stirred for about 30 minutes at a temperature of about 35-45 0 C and then over the next 30 minutes to an hour the solution is cooled to a temperature of about 0 to 10 0 C.
  • the mixture is held at a temperature of 0 to 10 0 C for an additional 30 minutes to an hour and then filtered to recover the pure levetiracetam product solids.
  • the solids are washed with acetone, which has been cooled to a temperature of about 0 to 10 0 C, and then the solids are dried on the filter with vacuum and nitrogen. The solids are further dried at a temperature of 60 to 70 0 C under a vacuum ( ⁇ 20 in. Hg) for 8 to 12 hours to yield the final purified levetiracetam product.
  • the reaction mixture obtained in accordance with Example 1 is warmed to a temperature of 25 - 30 0 C and is filtered to remove any undissolved solids.
  • the recovered filter cake is washed with about 31 pbw of acetonitrile and the solids are discarded.
  • the wash liquid is combined with the filtrate and transferred to a flask equipped for a vacuum distillation.
  • the solution is concentrated to a volume of less than 20% of its original volume causing solids to form. It may be necessary to heat the contents of the flask to a temperature of 25 to 40 0 C during the distillation to obtain the desired volume reduction.
  • the distillate is discarded and about 54 pbw of ethyl acetate is added to the flask.
  • the contents of the flask are stirred and then vacuum concentration is initiated again.
  • the volume is once again reduced to less than 20% of its original volume, in an attempt to remove all of the solvent.
  • the vacuum is released and the residual mixture is cooled to a temperature less 30 0 C.
  • the distillate is discarded.
  • about 178 pbw of ethyl acetate is added to the flask and the contents of the flask are heated to a temperature of 70 - 80 0 C to dissolve the solids. Once the solids have dissolved the solution is subjected to a controlled cooling. First, the mixture is cooled to a temperature of about 35 - 45 0 C and held for about 30 to 60 minutes.
  • reaction mixture is cooled further to a temperature of about 0 - 10 0 C over a period of about 30 - 60 minutes and then is held at that temperature for about 30 - 60 minutes.
  • the resulting slurry is filtered and the filtrate is discarded.
  • the solids are washed further with about 107 pbw of cold ethyl acetate (0 - 10 0 C) and the solids are dried at a temperature of about 60 - 70 0 C under a vacuum ( ⁇ 20 in. Hg)) for 8-12 hours.
  • the crude product is expected to contain about 65-68 pbw of crude levetiracetam.
  • the mixture is cooled to a temperature of about 0- 10 C over a period of about 30 - 60 minutes and then the mixture is held at that temperature with mixing for about 30 - 60 minutes.
  • the pure levetiracetam should precipitate from the solution and the slurry is filtered to collect the pure levetiracetam solids.
  • the filter cake is washed with about 50 pbw of cold (0 - 10 0 C) acetone. The filtrate and wash liquid from both steps are discarded.
  • the levetiracetam wet cake is dried at a temperature of 60 - 70 0 C under a vacuum ( ⁇ 20 in. Hg) for 8 - 12 hours.
  • the pure product is expected to contain about 52-55 pbw of levetiracetam.

Landscapes

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

Abstract

La présente invention a pour objet une méthode de synthèse améliorée du (S)-α-éthyl-2-oxo-1-pyrrolidineacétamide (également connu sous le nom de lévétiracétam) à partir de l'acide (S)-α-éthyl-2-oxo-1-pyrrolidineacétique (acide lévo) dans laquelle l'acide (S)-α-éthyl-2-oxo-1-pyrrolidineacétique (acide lévo) est mis au contact de di-tert-butyldicarbonate, de bicarbonate d'ammonium et de pyridine dans un solvant tel que l'acétonitrile afin de former le lévétiracétam.
PCT/US2006/018462 2005-05-24 2006-05-12 SYNTHÈSE DU (S)-α-ÉTHYL-2-OXO-1-PYRROLIDINEACÉTAMIDE WO2006127300A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US68379605P 2005-05-24 2005-05-24
US60/683,796 2005-05-24

Publications (1)

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WO2006127300A1 true WO2006127300A1 (fr) 2006-11-30

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Country Status (1)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6903130B1 (en) * 1999-12-01 2005-06-07 Ucb S.A. Pyrrolidineacetamide derivative alone or in combination for treatment of cns disorders

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6903130B1 (en) * 1999-12-01 2005-06-07 Ucb S.A. Pyrrolidineacetamide derivative alone or in combination for treatment of cns disorders

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