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WO2023100110A1 - Procédé de préparation de brivaracétam - Google Patents

Procédé de préparation de brivaracétam Download PDF

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Publication number
WO2023100110A1
WO2023100110A1 PCT/IB2022/061610 IB2022061610W WO2023100110A1 WO 2023100110 A1 WO2023100110 A1 WO 2023100110A1 IB 2022061610 W IB2022061610 W IB 2022061610W WO 2023100110 A1 WO2023100110 A1 WO 2023100110A1
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WO
WIPO (PCT)
Prior art keywords
oxo
propylpyrrolidine
carboxylic acid
acid
yield
Prior art date
Application number
PCT/IB2022/061610
Other languages
English (en)
Inventor
Daniel Coughlin
Jeremy WILT
Original Assignee
Macfarlan Smith 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 Macfarlan Smith Limited filed Critical Macfarlan Smith Limited
Publication of WO2023100110A1 publication Critical patent/WO2023100110A1/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
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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 present invention relates to a novel compound, (4R)-l-((S)-l-carboxypropyl)-2-oxo-4- propylpyrrolidine-3 -carboxylic acid, which can be used as an intermediate in the preparation of brivaracetam.
  • the invention is also directed to processes for preparing intermediates used in the preparation of brivaracetam.
  • Brivaracetam has the following structure:
  • BRIVIACT® Brivaracetam
  • BRIVIACT® Brivaracetam
  • 2S 2-[(4R)-2-oxo-4-propyltetrahydro-lH-pyrrol-l-yl] butanamide.
  • Its molecular formula is C11H20N2O2 and its molecular weight is 212.29.
  • BRIVIACT® is indicated for the treatment of partial-onset seizures in patients 1 month of age and older.
  • brivaracetam processes for the preparation of brivaracetam, such as U.S. Patent Nos. 7,629,474; 8,076,493; and 8,957,226.
  • Various publications also disclose processes for the preparation of brivaracetam, such as Kenda et al, J. Med. Chem. 2004, 47, 530, “Discovery of 4- substituted pyrrolidone butanamides as new agents with significant antiepileptic activity.”
  • these published syntheses describe the use of chiral or conventional chromatography or low yielding diastereomeric crystallizations to synthesize brivaracetam with the correct chirality of the two contained chiral centers, and thus are unattractive for scale-up.
  • the present invention is directed to a novel compound, (4R)-l-((S)-l-carboxypropyl)-2-oxo-4- propylpyrrolidine-3 -carboxylic acid, which can be used as an intermediate in the preparation of brivaracetam.
  • the invention is also directed to a process of preparing (4R)-1-((S)-1- carboxypropyl)-2-oxo-4-propylpyrrolidine-3-carboxylic acid.
  • the invention is directed to P100183W001 a process of preparing (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl)butanoic acid from (4R)-1-((S)-
  • the term “about” or “approximately” means within 1, 2, 3 or 4 standard deviations.
  • the term “about” or “approximately” means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range.
  • ambient temperature or “room temperature” means between about 15 °C to about 30 °C, such as about 15 °C to about 25 °C.
  • One embodiment of the invention is directed to (4R)-l-((S)-l-carboxypropyl)-2-oxo-4- propylpyrrolidine-3 -carboxylic acid, as depicted in Formula I:
  • Another embodiment of the invention is directed to use of a compound of Formula I in preparing brivaracetam.
  • Formula I comprising reacting a suspension of (4R)-2-oxo-4-propylpyrrolidine-3 -carboxylic acid with a solution of (R)-2-bromobutanoic acid as depicted below.
  • a solution of (4R)-2-oxo-4-propylpyrrolidine-3-carboxylic acid in an organic solvent is added to a suspension of base in an organic solvent to yield the suspension of (4R)-2-oxo-4-propylpyrrolidine-3-carboxylic acid.
  • the organic solvent is P100183W001 selected from 2-MeTHF, 1,4-dioxane, MTBE, DMSO, CH3OH, and THF.
  • the organic solvent is THF.
  • the organic solvent in the solution of (4R)-2-oxo-4- propylpyrrolidine-3 -carboxylic acid and in the suspension of base can be the same or different.
  • the organic solvent is the same. In one embodiment, about 8-10 volumes (mL), particularly about 8.5 volumes, of organic solvent are used per weight (g) of base in the suspension of base. In one embodiment, the base is selected from t-BuOK, CHsONa, CS2CO3, K2CO3, NaOH, and LiOH. In a particular embodiment, the base is NaOH. In one embodiment, about 15-25 volumes (mL), particularly about 20 volumes, of organic solvent are used per weight (g) of (4R)-2-oxo-4-propylpyrrolidine-3 -carboxylic acid in the solution of (4R)- 2-oxo-4-propylpyrrolidine-3 -carboxylic acid.
  • the molar ratio of (4R)-2-oxo- 4-propylpyrrolidine-3-carboxylic acid to base is about l:4.5-6.5, particularly, about 1:5.
  • the solution of (4R)-2-oxo-4-propylpyrrolidine-3 -carboxylic acid is added dropwise to the suspension of base for about 10-20 minutes, particularly for about 15 minutes.
  • the resulting suspension is stirred at about 35-45 °C, particularly at about 40 °C, for about 20-40 minutes, particularly for about 30 minutes.
  • the solution of (R)-2-bromobutanoic acid comprises (R)-2-bromobutanoic acid in an organic solvent.
  • the organic solvent is selected from 2-MeTHF, 1,4-dioxane, MTBE, DMSO, CH3OH, and THF. In a particular embodiment, the organic solvent is THF. In one embodiment, about 8-12 volumes (mL), particularly about 10 volumes, of organic solvent are used per weight (g) of (R)-2-bromobutanoic acid in the solution of (R)-2-bromobutanoic acid. In one embodiment, the solution of (R)-2-bromobutanoic acid is added to the suspension of (4R)-2-oxo- 4-propylpyrrolidine-3-carboxylic acid.
  • the solution of (R)-2- bromobutanoic acid is added dropwise over about 1.5-2.5 hours, particularly over about 2 hours.
  • the molar ratio of (4R)-2-oxo-4-propylpyrrolidine-3-carboxylic acid to (R)- 2-bromobutanoic acid is about 1 :2.
  • the reaction mixture containing the suspension of (4R)-2-oxo-4-propylpyrrolidine-3 -carboxylic acid and solution of (R)-2- bromobutanoic acid is stirred at about 35-45 °C, particularly at about 40 °C, for about 12-22 hours, particularly for about 15 hours.
  • reaction mixture does not stir easily, additional organic solvent may be added to facilitate stirring.
  • the reaction mixture is cooled to room temperature.
  • the reaction mixture is concentrated to remove the organic solvent.
  • water is added after concentration.
  • P100183W001 about 25-35 volumes (mL), particularly about 30 volumes, of water are added per weight (g) of (4R)-2-oxo-4-propylpyrrolidine-3-carboxylic acid starting material.
  • the resulting mixture after addition of water is washed with DCM.
  • the mixture is washed 2 or 3 times, particularly 3 times.
  • the pH of the aqueous solution is adjusted to about 1-2.
  • the pH is adjusted with aqueous HC1.
  • the pH is adjusted with 4 M aqueous HC1.
  • the mixture is extracted with EA, resulting in aqueous and organic phases.
  • the mixture is extracted 2-4 times, particularly 4 times.
  • the organic phases are combined.
  • the organic phases are dried over MgSCh and concentrated to yield an oil.
  • the oil is dissolved is an organic solvent selected from 2-MeTHF, 1,4-dioxane, MTBE, DMSO, and CH3OH.
  • the solvent is MTBE.
  • about 1.5-2 volumes (mL) of organic solvent are used per weight (g) of oil.
  • an antisolvent is added to the dissolved oil.
  • the anti-solvent is heptane. In one embodiment, about 8-12 volumes (mL) of antisolvent are added per weight (g) of oil. In one embodiment, the anti-solvent is added dropwise over about 30 minutes. In one embodiment, the mixture is stirred at room temperature for about 2-5 hours, particularly for about 3.5 hours. In one embodiment, the precipitate is collected by filtration. In one embodiment, the precipitated solid is recrystallized. In one embodiment, the precipitated solid is dissolved in an organic solvent selected from in 2-MeTHF, 1,4-dioxane, MTBE, DMSO, and CH3OH. In one embodiment, the solvent is MTBE.
  • the antisolvent is added to the dissolved solid.
  • the anti-solvent is heptane.
  • about 14-18 volumes (mL), particularly about 16 volumes, of anti-solvent are added per weight (g) of dissolved solid.
  • the anti-solvent is added dropwise over about 30 minutes.
  • the mixture is stirred at RT for about 12-24 hours, particularly for about 17 hours, to yield a P100183W001 compound of Formula I.
  • the compound of Formula I may be isolated by any means known to one of skill in the art. In one embodiment, the compound of Formula I is isolated by filtration.
  • Another embodiment of the invention is directed to a process of preparing (S)-2-((R)-2-oxo-4- propylpyrrolidin-l-yl)butanoic acid by heating a mixture of (4R)-l-((S)-l-carboxypropyl)-2-oxo- 4-propylpyrrolidine-3-carboxylic acid in an organic solvent as depicted below.
  • the organic solvent is DMF or 1,4-di oxane. In a particular embodiment, the organic solvent is DMF. In one embodiment, about 8-12 volumes (mL), particularly about 10 volumes, of organic solvent are used per weight (g) of (4R)-l-((S)-l-carboxypropyl)-2-oxo-4- propylpyrrolidine-3 -carboxylic acid. In one embodiment, the mixture of (4R)-1-((S)-1- carboxypropyl)-2-oxo-4-propylpyrrolidine-3-carboxylic acid in an organic solvent is heated to at least about 75 °C, particularly greater than about 100 °C.
  • the mixture of (4R)- l-((S)-l-carboxypropyl)-2-oxo-4-propylpyrrolidine-3-carboxylic acid in an organic solvent is heated to about 105 °C in an oil bath.
  • the mixture of (4R)-1-((S)-1- carboxypropyl)-2-oxo-4-propylpyrrolidine-3-carboxylic acid in an organic solvent is stirred while heating.
  • the heating is for about 20-50 hours. The heating time can be adjusted based on the yield of (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl) butanoic acid.
  • the reaction mixture is cooled to RT.
  • aqueous HC1 is added to the reaction mixture.
  • 1 M aqueous HC1 is added.
  • about 25-35 volumes (mL), particularly about 30 volumes, of 1 M HC1 aqueous solution is added per weight (g) of (4R)-l-((S)-l-carboxypropyl)-2-oxo-4-propylpyrrolidine-3 -carboxylic acid starting material.
  • the mixture is extracted with EA, resulting in aqueous and organic phases.
  • the mixture is extracted 2-4 times, particularly 3 times, with EA.
  • the organic phases are combined and washed with a LiCl aqueous solution.
  • the LiCl aqueous solution is 5% LiCl.
  • the combined organic phase is washed more than one time, particularly 5 times.
  • aqueous LiCl is used per weight (g) of (4R)-l-((S)-l-carboxypropyl)-2-oxo-4-propylpyrrolidine-3-carboxylic acid starting material.
  • the organic phase is dried over MgSCh and concentrated to yield a solid.
  • the solid is optionally recrystallized.
  • the solid is dissolved in an organic solvent, such as EA, MTBE, toluene, 2-MeTHF, and THF.
  • the solvent is EA.
  • about 2 volumes of solvent (mL) are used per weight (g) of solid.
  • an antisolvent is added to the dissolved solid.
  • the anti-solvent is heptane.
  • about 1-14 volumes (mL), particularly about 12 volumes, of anti-solvent are added per weight (g) of solid.
  • the anti-solvent is added dropwise.
  • the mixture is stirred. In a particular embodiment, the mixture is stirred at RT for about 12-24 hours, particularly for about 17 hours, and at 0-5 °C for about 1-3 hours, particularly for about 2 hours, to yield (S)-2-((R)-2- oxo-4-propylpyrrolidin-l-yl)butanoic acid as a precipitate.
  • the (S)-2-((R)-2-oxo-4- propylpyrrolidin-l-yl)butanoic acid may be isolated by any means known to one of skill in the art. In one embodiment, the (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl)butanoic acid is isolated by filtration.
  • the (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl)butanoic acid is optionally recrystallized with an organic amine.
  • the organic amine is propan-2-amine or cyclohexylamine.
  • the organic amine is cyclohexylamine.
  • crude (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl) butanoic acid is dissolved in an organic solvent such as EA, MTBE, and ACN.
  • the solvent is EA.
  • about 4-6 volumes, particularly about 5 volumes, of organic solvent are used per weight (g) of (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl)butanoic acid.
  • the organic amine is added to the dissolved (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl)butanoic acid.
  • the molar ratio of (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl) butanoic acid to the organic amine is about 1: 1.5.
  • the organic amine is added drop wise.
  • the resulting mixture is stirred at RT for about 6-8 hours, particularly for about 6.5 hours, to yield the amine salt of (S)-2-((R)-2-oxo-4-propylpyrrolidin-l-yl)butanoic acid as a precipitate.
  • the precipitate may be isolated by any means known to one of skill in the art. In one embodiment, the precipitate is isolated by filtration. P100183W001
  • the above combined HC1 aqueous solution is adjusted to pH 8 - 9. Some solid precipitates out and the solid is collected by filtration and the crude solid is re-slurried in IPA (20 mL) and an off-white solid is collected by filtration ( ⁇ 2.4 g). The aqueous filtrate is extracted with DCM (4 x 30 mL), dried over MgSCh and concentrated to give a brown oil. A mixture of the crude oil in IPA (15 mL) is stirred at RT for 1.5 h and some amount of solid precipitates out. The mixture is filtered to yield an off-white solid ( ⁇ 0.9 g).
  • a mixture of dimethyl (R)-2-(l-nitropentan-2-yl)malonate (195 g, assay 48.7%, the amount of pure dimethyl (R)-2-(l-nitropentan-2-yl)mal onate is 95 g), iron powder (2.0 g) and Pd/C (10% palladium on carbon with 57% H2O, 9.5 g) in CH3OH (665 mL) is hydrogenated at 45 °C and 0.5 MPa of H2 in a 1 L autoclave for 10 h.
  • the reaction is concentrated to remove CH3OH and the residual is washed with DCM (2 x 100 mL), then the pH of the aqueous solution is adjusted to 1-2 by 4 M HC1 aqueous solution. The resulting aqueous solution is extracted with EA (4 x 100 mL). The combined organic phase is dried over Na2SO4 and concentrated to give a light yellow oil in 99.0% purity and 99% yield (38 g).
  • the resulting mixture is extracted with EA (4 x 400 mL). The combined organic phase is dried over MgSCh and concentrated to give a light yellow oil (84 g).
  • the crude oil is dissolved in MTBE (168 mL) and heptane (840 mL) is added dropwise over 0.5 h and some amount of oily product is observed during the addition process of heptane.
  • the mixture is stirred at RT and some amount of solid is precipitated out after about 1.5 h.
  • the suspension is stirred at RT for another 2 h and an off-white solid is collected by filtration (53 g wet weight).
  • the solid is dissolved in MTBE (168 mL) and heptane (840 mL) is added dropwise over 0.5 h.
  • the mixture is stirred at RT for 17 h and filtered to yield an off-white solid in 86.4% purity and 74.4% yield (45.8 g).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un nouveau composé, de l'acide de (4R)-1-((S)-1-carboxypropyl)-2-oxo-4-propylpyrrolidine-3-carboxylique, qui peut être utilisé comme intermédiaire dans la préparation de brivaracétam. L'invention concerne également un procédé de préparation de l'acide (4R)-1-((S)-1-carboxypropyl)-2-oxo-4-propylpyrrolidine-3-carboxylique. En outre, l'invention concerne un procédé de préparation de l'acide (S)-2-((R)-2-oxo-4-propylpyrrolidin-1-yl)butanoïque à partir de l'acide (4R)-1-((S)-1-carboxypropyl)-2-oxo-4-propylpyrrolidine-3-carboxylique. L'acide (S)-2-((R)-2-oxo-4-propylpyrrolidin-1-yl)butanoïque peut également être utilisé dans un procédé de préparation de brivaracétam.
PCT/IB2022/061610 2021-12-02 2022-11-30 Procédé de préparation de brivaracétam WO2023100110A1 (fr)

Applications Claiming Priority (2)

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US202163264816P 2021-12-02 2021-12-02
US63/264,816 2021-12-02

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007065634A1 (fr) * 2005-12-07 2007-06-14 Ucb Pharma, S.A. Derives de la 3-carboxy-2-0x0-1-pyrrolidine et leurs utilisations
EP1806339A1 (fr) * 2005-12-21 2007-07-11 Ucb, S.A. Procédé de préparation de dérivés 2-oxo-1-pyrrolidine
US7629474B2 (en) 2003-09-24 2009-12-08 Ucb Pharma S.A. Process for preparing 2-oxo-1-pyrrolidine derivatives
US8957226B2 (en) 2005-09-15 2015-02-17 Ucb Pharma S.A. 2-oxo-1-pyrrolidine derivatives, processes for preparing them and their uses
CN115141134A (zh) * 2021-03-31 2022-10-04 江西同和药业股份有限公司 一种化合物及其制备方法和应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7629474B2 (en) 2003-09-24 2009-12-08 Ucb Pharma S.A. Process for preparing 2-oxo-1-pyrrolidine derivatives
US8957226B2 (en) 2005-09-15 2015-02-17 Ucb Pharma S.A. 2-oxo-1-pyrrolidine derivatives, processes for preparing them and their uses
WO2007065634A1 (fr) * 2005-12-07 2007-06-14 Ucb Pharma, S.A. Derives de la 3-carboxy-2-0x0-1-pyrrolidine et leurs utilisations
US8076493B2 (en) 2005-12-07 2011-12-13 Ucb Pharma, S.A. 3-carboxy-2-oxo-1-pyrrolidine derivatives and their uses
EP1806339A1 (fr) * 2005-12-21 2007-07-11 Ucb, S.A. Procédé de préparation de dérivés 2-oxo-1-pyrrolidine
CN115141134A (zh) * 2021-03-31 2022-10-04 江西同和药业股份有限公司 一种化合物及其制备方法和应用

Non-Patent Citations (2)

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Title
DATABASE Reaxys [online] Elsevier Life Sciences IP Limited; 4 October 2022 (2022-10-04), YANG FENG ET AL.: "Compound as well as preparation method and application thereof", XP093022727, Database accession no. 61447313 (Rx-ID), 44171798 (XRN) *
KENDA ET AL., J. MED. CHEM., vol. 47, 2004, pages 530

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