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WO2017076737A1 - Procédé continu de préparation de brivaracétam - Google Patents

Procédé continu de préparation de brivaracétam Download PDF

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Publication number
WO2017076737A1
WO2017076737A1 PCT/EP2016/075934 EP2016075934W WO2017076737A1 WO 2017076737 A1 WO2017076737 A1 WO 2017076737A1 EP 2016075934 W EP2016075934 W EP 2016075934W WO 2017076737 A1 WO2017076737 A1 WO 2017076737A1
Authority
WO
WIPO (PCT)
Prior art keywords
reactor
propyl
process according
butanamide
pyrrolidinyl
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/EP2016/075934
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English (en)
Inventor
Edith NORRANT
Didier NUEL
Laurent GIORDANO
Julien Leclaire
Jean SEPTAVAUX
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.)
UCB Biopharma SRL
Original Assignee
UCB Biopharma SRL
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 UCB Biopharma SRL filed Critical UCB Biopharma SRL
Publication of WO2017076737A1 publication Critical patent/WO2017076737A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • Brivaracetam ((2S)-2-((4R)-2-oxo-4-n-propyl-1 -pyrrolidinyl) butanamide (I), is anti-epileptic that was first disclosed in WO 01/62726.
  • Step 1 Obtention of 5-hydroxy-4-n-propyl-furan-2-one through condensation of valeraldehyde with glyoxylic acid :
  • Step 2 Obtention of (2S)-2-((4R)-2-oxo-4-n-propyl-1-pyrrolidinyl)butanamide and (2S)- 2-((4S)-2-oxo-4-n-propyl-1-pyrrolidinyl)butanamide
  • Said step 2 combines the reductive amination step as well as the hydrogenolysis step disclosed in WO 01/62726 in a one-pot reaction.
  • the individual diastereomers obtained therefrom may then be separated, e.g. through chiral MCC.
  • the batch process is a single- or multi-stage process in which a certain quantity of inputs (starting materials, solvents, catalysts, energy, etc.) are fed into the chemical reaction unit (of the entire reaction) under conditions suitable for obtaining the desired reaction
  • the batch process can be undertaken in one reactor in which all the actions are carried out one after the other, or in a series of reactors in each of which a different stage of the process is carried out.
  • the quality of the end product may be controlled by the addition of appropriate separation stages between the various other stages as required. Reactants that do not react, being then separated from the reaction mixture, may be returned for a further reaction (usually after they have undergone a purification step), thus maximizing yield.
  • the continuous flow process is one in which inputs are fed into the system at a constant rate and at predefined ratios (starting materials, solvents, catalysts, energy, etc.), and at the same time, a permanent extraction of outputs (final products) is performed (products, by-products, energy, etc.).
  • starting materials, solvents, catalysts, energy, etc. starting materials, solvents, catalysts, energy, etc.
  • final products final products
  • products, by-products, energy, etc. a series of reaction steps are performed in separate but connected flow reactors that are individually and sequentially fed and evacuated in such a way that continuous flow of starting products, intermediate and final products in the integrated system is achieved.
  • Such method is characterized by a constant process taking place in each section (flow reactor) of the integrated facility and during the time of its action a constant process takes place.
  • the concentration of reactants and products at every location in the system is in a durable state and control of the process is done by maintaining these concentrations.
  • Each of the production methods (batch/continuous) has its own characteristics. In the batch process, the shift from one stage to the next is carried out in series and so the overall time of the process is, in fact, the sum of the times required for the various stages, and it is relatively extensive.
  • micro-reactors might be regarded as the chemist's round-bottomed flask of the 21 st century. Micro-reactors are generally operated in a continuous flow mode.
  • flow chemistry allows the scale-independent synthesis from g to kg amounts in a single day.
  • the small reactor volume facilitates the safe and easy handling of hazardous or instable materials and highly exothermic reactions.
  • Fast and easy parameter screening makes micro-reactor technology an ideal tool for process development.
  • the initial investment for continuous process plants tend to be less significant compared to batch installations, due to the size of batch reactors which are bigger, even if the automated control systems is more important.
  • the overall Capex spending shows though a clear advantage for the continuous approach.
  • final products required in large quantities and to be manufactured throughout a 12-month period the continuous process would be first choice.
  • final products required in small amounts, or alternatively, for which the annual demand varies the batch process is the preferred approach by many but not for all companies.
  • the objective of the present invention consists in the provision of a more economical approach for preparing brivaracetam; ideally such process would be more cost-effective, produce less waste products and would be safe from a chemical engineering point of view.
  • the present invention relates to a new method for the preparation of brivaracetam, said method comprises an integrated continuous flow process for reactions wherein a
  • Figure 1 A shows a flow-chart, illustrating one embodiment of how to run an integrated, continuous flow with batch workup of the method according to the present invention.
  • Figure 1 B shows flow-charts illustrating by example step 1 of the present invention, where glyoxylic acid (1 .2 eq) at a temperature of 70°C and valeraldehyde acid (1 eq) are both added into a flow reactor to get hydroxyfuranone to be used in the process set out in Figure 1 A.
  • the reaction is done in only one reactor or to improve the yield we can add a second reactor to transform Form E into hydroxyfuranone in the second reactor using different operating conditions.
  • Figure 1 C shows a flow-chart, illustrating by example step 2 of the present invention, which is composed with 3 consecutive reactions.
  • Figure 1 D shows the continuous gas/liquid/solid reactors used for hydrogenation reaction
  • the present invention relates to an integrated, continuous flow method for the preparation of brivaracetam for reactions with batch system for work-up.
  • Said method comprises three major chemical synthetic steps, performed in a succession of flow reactors that are connected in such a way to give an integrated flow manufacturing system with batch work-up.
  • One aspect of the invention consists in the fact that 3 steps - set out in WO 2005/ 028435 - starting from valeraldehyde and glyoxylic acid leading to the diasteromers (2S)-2-((4R)-2-oxo-4-n-propyl-1-pyrrolidinyl)butanamide (lb) and (2S)-2-((4S)-2-oxo-4- n-propyl-1 -pyrrolidinyl)-butanamide (la) are performed in an integrated continuous flow process, whereby each step is performed in several flow reactors. All flow reactors are connected with batch equipment to get the right purity before introducing the flow in the next following continuous reaction step.
  • the method thus comprises the following 3 steps :
  • Step 1 Synthesis of 5-hydroxy-4-n-propyl-furan-2-one (II) :
  • Step 1 would typically be run, essentially without the use of any solvent, in one embodiment and without any catalyst at all (Neat reaction) in another embodiment.
  • the ratio of the glyoxylic acid / valeraldehyde mixture would be typically about 1 .1 /1 , up to 1.5/1 and preferably between 1 .2/1 and 1.3/1 .
  • the residence time of said mixture in the reactor x s is typically anywhere between 1 and 20 minutes, preferably about 2-10 minutes depending on the temperature.
  • a purification within said flow reactor may be performed after step 1 is completed, e.g.
  • the conversion rate of valeraldehyde obtained is typically between 90-100 %, preferably up to 100%.
  • the overall yield for 5-hydroxy-4-n-propyl-furan-2-one is about 85-93%.
  • Step 2 Synthesis of (2S)-4,5-dehydro-(2-oxo-4-n-propyl-1 -pyrrolidinyl)-2-butanamide (III):
  • Step 2 comprises the condensation of S-aminobutyric amide with 5-hydroxy-4-n-propyl- furan-2-one (II) in ethanol obtained from step 1 , at temperatures ranging from 30-50°C, preferably at 40°C during 5 minutes, followed by addition of a mixture of NaBH 4 / NH 3 at a temperature of 30-50°C, preferably about 40°C, during up to 10 minutes
  • the lactam is extracted through addition of either of the following solvents EtOAc, i-PrOAc MIPK, t-BuOAc or mixtures thereof.
  • EtOAc which may also help to remove salts.
  • Such extraction is typically performed at room temperature (20-25°C).
  • Step 2 3 consecutive reactions are achieved in one single flow in 3 different types of continuous reactors :
  • the overall yield for the 3 consecutive reactions in Step 2 is up to 96% in a continuous process that takes less than 30mn.
  • Step 3 Synthesis of (2S)-2-((4R)-2-oxo-4-n-propyl-1-pyrrolidinyl)butanamide (lb) through catalytic reduction
  • the catalytic reduction is performed in a solvent, typically in water using the Pd/C catalyst system ("Catalyst"; which are commercially available) or Pd/CaC0 3 .
  • the hydrogen pressure is usually adjusted at below about 20 bar, preferably below 15, more preferably below 10 bar.
  • Catalyst the following catalytic systems
  • TTT stands for triazine trithiol trisodium and has the following structure :
  • a chromatographic separation may be performed.
  • the chromatographic separation of the two diastereoisomers (la) and (lb) obtained in step 3 is performed using of
  • All the reactors in step 3 described in figure 1 D are performed in flow reactors connected to each other in such a way to provide an integrated system.
  • a continuous flow reactor is preferred.
  • This reactor consist in several (about 5) separately controlled CSTR reactors in series.
  • Each reactor is equipped with a Rushton self-gas-inducing agitator affording a very high gas-liquid transfer and a filter at the outlet to prevent the catalyst from leaving the each reactor.
  • the reaction conditions (stirrer speed, Hydrogen pressure, internal temperature, etc ..) in each reactor could be set and monitored separately, allowing the reactor to fit the need.
  • the temperature used in each module of reactor can be adapted at the kinetic rate of reaction
  • the volume of reactor, made of Hastelloy C is close to 6.2ml.
  • S-ABA free base in EtOH solvent (0.4mol/l) and (dried) hydroxyfuranone ( coming from step 1 ) are introduced separately and in continuous plug flow the reactor with a molar ratio S-ABA free base /Hydroxyfuranone equal to 1.2.
  • the temperature in the first plug flow reactor is 40°C and the residence time is 5mn.
  • the mixture coming out from this first reactor is introduced continuously in well mixed reactor in which it is added continuously NaBH4 (0.4 eq of Hydroxyfuranone) with NH3 at 0.1 M.
  • the global yield is 96% before the workup.
  • the purification of crude lactam is done by several extractions, for example by EtOAc , MEK, or l-PrOAc in batch way.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé en flux continu pour préparer du brivaracétam.
PCT/EP2016/075934 2015-11-03 2016-10-27 Procédé continu de préparation de brivaracétam Ceased WO2017076737A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP15192758 2015-11-03
EP15192758.9 2015-11-03

Publications (1)

Publication Number Publication Date
WO2017076737A1 true WO2017076737A1 (fr) 2017-05-11

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PCT/EP2016/075934 Ceased WO2017076737A1 (fr) 2015-11-03 2016-10-27 Procédé continu de préparation de brivaracétam

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019157856A1 (fr) * 2018-02-13 2019-08-22 扬州奥锐特药业有限公司 Procédé de préparation d'un intermédiaire de lactame et de brivaracétam de haute pureté chirale
WO2020052545A1 (fr) * 2018-09-12 2020-03-19 上海宣泰医药科技有限公司 Procédé de préparation de brivaracétam et ses intermédiaires
CN111187175A (zh) * 2020-01-08 2020-05-22 上海朴颐化学科技有限公司 一种利用微通道反应器氢化制备布瓦西坦的中间体的方法
CN111848486A (zh) * 2020-07-16 2020-10-30 赤峰经方医药技术开发有限责任公司 一种制备乙磺酸尼达尼布的方法
JPWO2020175023A1 (ja) * 2019-02-28 2021-12-16 国立大学法人東京工業大学 アミドの製造方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001062726A2 (fr) 2000-02-23 2001-08-30 Ucb, S.A. Derives de 2-oxo-1-pyrrolidine, procedes de preparation et utilisations desdits derives
WO2005028435A1 (fr) 2003-09-24 2005-03-31 Ucb, S.A. Methode de preparation de derives de 2-oxo-1-pyrrolidine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001062726A2 (fr) 2000-02-23 2001-08-30 Ucb, S.A. Derives de 2-oxo-1-pyrrolidine, procedes de preparation et utilisations desdits derives
WO2005028435A1 (fr) 2003-09-24 2005-03-31 Ucb, S.A. Methode de preparation de derives de 2-oxo-1-pyrrolidine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BOURGUIGNON ET AL., THE JOURNAL OF ORGANIC CHEMISTRY, vol. 46, no. 24, 1981, pages 4889
BOURGUIGNON, J. J. ET AL.: "LACTONE CHEMISTRY. SYNTHESIS OF BETA-SUBSTITUTED, GAMMA- FUNCTIONALIZED BUTANOLIDES AND BUTENOLIDES AND SUCCINALDEHYDIC ACIDS FORM GLYOXYLIC ACID", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 46, no. 24, 1981, pages 4889, XP002024942, DOI: 10.1021/jo00337a013 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019157856A1 (fr) * 2018-02-13 2019-08-22 扬州奥锐特药业有限公司 Procédé de préparation d'un intermédiaire de lactame et de brivaracétam de haute pureté chirale
US11952341B2 (en) 2018-02-13 2024-04-09 Yangzhou Aoruite Pharmaceutical Co., Ltd. Method of preparing high chiral purity lactam intermediate and brivaracetam
WO2020052545A1 (fr) * 2018-09-12 2020-03-19 上海宣泰医药科技有限公司 Procédé de préparation de brivaracétam et ses intermédiaires
CN112739683A (zh) * 2018-09-12 2021-04-30 上海宣泰医药科技股份有限公司 布瓦西坦的制备方法及其中间体
CN112739683B (zh) * 2018-09-12 2024-04-16 上海宣泰医药科技股份有限公司 布瓦西坦的制备方法及其中间体
JPWO2020175023A1 (ja) * 2019-02-28 2021-12-16 国立大学法人東京工業大学 アミドの製造方法
CN111187175A (zh) * 2020-01-08 2020-05-22 上海朴颐化学科技有限公司 一种利用微通道反应器氢化制备布瓦西坦的中间体的方法
CN111848486A (zh) * 2020-07-16 2020-10-30 赤峰经方医药技术开发有限责任公司 一种制备乙磺酸尼达尼布的方法

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