[go: up one dir, main page]

WO2020148731A1 - Procédé de préparation d'intermédiaires de brivaracétam et leur utilisation - Google Patents

Procédé de préparation d'intermédiaires de brivaracétam et leur utilisation Download PDF

Info

Publication number
WO2020148731A1
WO2020148731A1 PCT/IB2020/050391 IB2020050391W WO2020148731A1 WO 2020148731 A1 WO2020148731 A1 WO 2020148731A1 IB 2020050391 W IB2020050391 W IB 2020050391W WO 2020148731 A1 WO2020148731 A1 WO 2020148731A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
salts
acid
iii
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/IB2020/050391
Other languages
English (en)
Inventor
Venkateshwar Kumar Thaduri
Venugopala Rao BANDI
Venkateshwara Rao KADALI
Venkata Rao TANNEERU
Thirupathi KANDALA
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.)
Stereokem Pvt Ltd
Original Assignee
Stereokem Pvt 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 Stereokem Pvt Ltd filed Critical Stereokem Pvt Ltd
Publication of WO2020148731A1 publication Critical patent/WO2020148731A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • 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
    • C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide

Definitions

  • the present invention relates to a process for preparation of antiepileptic agent intermediates.
  • the present invention particularly relates to a process for preparation of Brivaracetam intermediates.
  • the present invention relates to a process for preparation of Brivaracetam compound of Formula (I)
  • Brivaracetam is an antiepileptic drug for the treatment of partial-onset seizures with or without secondary generalisation, in combination with other antiepileptic drugs. Brivaracetam is approved by USFDA in May 2016. Brivaracetam is a racetam derivative with anticonvulsant properties and is 4-n- propyl analog of Levetiracetam. Brivaracetam is chemically known as (2S)-2-[(4R)-2- oxo-4-propylpyrrolidinyl] butanamide. Its empirical Formula is C I I H 2O N 2 0 2 and the molecular weight is 212.29. The structural Formula is:
  • X ! is— CONR 4 R 5 ,— COOH,— COOR 3 or— CN
  • X 2 is— CONR 4 R 5 ,—COOH,— COOR 3 or— CN.
  • W02016075082 discloses a process for preparing Brivaracetam intermediate compound is as shown below:
  • the present invention is to provide a simple, economical and commercially feasible process for the synthesis of Brivaracetam intermediates with a commercially acceptable yield and high purity. It is therefore an object of the present inventors have invented a process for preparation of Brivaracetam is of yield and high purity comprising the process for preparation of intermediates.
  • the main objective of the present invention is to provide a process for preparation of Brivaracetam intermediates.
  • In another objective of the present invention is to provide a process for the preparation of Brivaracetam intermediates, which is commercially feasible / industrially scalable.
  • the present invention provides a process for the preparation of compound of Formula (II)
  • the present invention provides a process for the preparation of compound of Formula (IIA)
  • the present invention provides a process for the preparation of compound of Formula (III)
  • the present invention provides a process for the preparation of compound of Formula (IV A)
  • the present invention provides a process for the preparation of compound of Formula (IIA)
  • the present invention provides a process for the preparation of compound of Formula (IIA)
  • the present invention provides a process for the preparation of compound of Formula (IIB) Formula (IIB)
  • the present invention provides a process for the preparation of compound of Formula (VI) Formula (VI)
  • the present invention provides a process for the preparation of compound of Formula (VI) Formula (VI)
  • the present invention provides a process for the preparation of compound of Formula (VI)
  • the present invention provides a process for the preparation of compound of Formula (IIB) Formula (IIB)
  • the present invention provides a process for the preparation of compound of Formula (IIB) Formula (IIB)
  • the present invention provides Brivaracetam compound of Formula (I)
  • the present invention provides Brivaracetam compound of Formula (I)
  • R is hydrogen
  • alkyl haloformate as used herein, where in alky group is a straight or branched, substituted or unsubstituted selected from Ci-C alky; and the halo group selected from chloro, bromo, fluoro or iodo.
  • the reagent as used herein such as 2-halobutanoic acid, wherein the halo group selected from chloro, bromo, fluoro or iodo.
  • the present invention provides a process for the preparation of compound of Formula (II) Formula (II) wherein R is hydrogen,
  • the present invention provides a process for the preparation of compound of Formula (IIA)
  • the present invention provides a process for the preparation of compound of Formula (III) Formula (III)
  • the present invention provides a process for the preparation of compound of Formula (IV A)
  • the present invention provides a process for the preparation of compound of Formula (IIA) Formula (IIA)
  • the present invention provides a process for the preparation of compound of Formula (IIA)
  • the present invention provides a process for the preparation of compound of Formula (IIB)
  • the present invention provides a process for the preparation of compound of Formula (VI) Formula (VI)
  • the present invention provides a process for the preparation of compound of Formula (VI)
  • the present invention provides a process for the preparation of compound of Formula (VI)
  • the present invention provides a process for preparation of Brivaracetam compound of Formula (I)
  • the present invention provides a process preparation of Brivaracetam compound of Formula (I) Formula (I)
  • Cyclization reaction of a compound of Formula (III) to compound of Formula (IIA) is carried out using an acid in presence of a suitable solvent.
  • the intermediates formed in the present invention may be isolated or not. Any of the above reactions may be carried out in-situ reactions to obtain compound of Formula (I) or its intermediates.
  • the above compounds may be isolated as salts or free bases, if the above compounds are isolated as salts they are converted to their free bases first and used for further reactions.
  • the compound of Formula (IIB) is prepared from compound of Formula (III) via compound of Formula (VI) which the process may or may not in-situ.
  • any of the reagents as used herein can be used catalytically or stoichiometrically.
  • the reagents are used in an amount from 1 to 10 equivalents.
  • the reactions in any of the steps of the present invention are carried out in the absence or presence of a solvent.
  • solvents used in the present invention are selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents” such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents” such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents” such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n
  • base used in the present invention is selected from either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof; alkyl metals such as n-butyl lithium or Silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, Lithium hexamethyldisilazide, Sodium hexamethyldisilazide and potassium hexamethyldisilazide or organic bases such as LDA (lithium diisoprop ylamide), triethylamine, triethanolaminetributylamine, N-methylmorpholine
  • salts refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature.
  • Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like.
  • Such salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene- 2-benzoate, bromide, isobutyrate, phenylbutyrate, beta-hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, nitrate, oxalate, phthalate, phosphate, monohydro genphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propionate, phenylpropionate, salicylate, succinate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite,
  • Acid used in the cyclization or in any of the reaction as used herein is selected from group of comprising of inorganic acid, organic acid, lewis acid or mixture thereof such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, perchloric acid, sulfuric acid, phosphoric acid (P2O5), poly phosphoric acid, camphorsulfonic acid, formic acid, acetic acid, acetic anhydride, trifluoroacetic acid, pTSA, citric acid and oxalic acid, propionic acid, butyric acid, pentanoic acid, isobutyric acid, hexanoic acid or mixture thereof.
  • inorganic acid organic acid, lewis acid or mixture thereof
  • inorganic acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, perchloric acid, sulfuric acid, phosphoric acid (P2O5), poly phosphoric acid, camphorsulfonic acid, formic acid, acetic acid, ace
  • the separated aqueous phase pH was adjusted to 2 to 2.5 with hydrochloric acid and extracted with toluene (lx 800 ml) at 70-80°C.
  • the separated toluene layer was washed with 10% sodium chloride solution (700ml) at the same temperature and allowed to crystallize the material. Filtered the solid 120 g (67%) and its optical purity 99.5 % by HPLC.
  • the toluene mother liquor was distilled off to 3 vol and 32.4 g acetylchloride was added.
  • the mixture was heated to 78-82°C and stirred for 5-6 hrs.
  • the reaction mixture was cooled to 50-60°C and water (300 ml) was added to separate the phases.
  • Toluene layer was added to the NaOH solution (12.5 g in 125 mL of water) and the mixture was heated to 78-82°C for 8-10 hrs. Cooled the reaction mixture to 25-30°C and the pH was adjusted to 1-3 with HC1.
  • Further toluene (350 ml) was added to the mixture and the phases were separated at 80°C.
  • the organic phase was cooled to 25- 30°C and filtered the solid. Re-crystallized from toluene to give the pure product which optical purity was 99.5%.
  • Step A Ethyl chloroformate (40 g, 0.368 mole) was added to a mixture of (3R)-3-[2- oxo-2-[[(lR)-l-phenylethyl]amino]ethylhexanoic acid (100 g, 0.360 mole) and triethylamine (38 g, 0.376 mole) in toluene at -10° to -20°C over a period of 40 min. The mixture was stirred for 1 hour at the same temperature followed by addition of solution of sodiumazide (28g, 0.430 mole in water). The mixture was stirred for 1 hour at -10° to -20°C and quenched over ice water.
  • Step B To the aq. solution of (R)-3-(Aminomethyl)hexanoic acid (33-35 gm) was added (R)-2-Bromo butyric acid (40 g) at 10-15°C and the mixture was stirred for 1 hour at the same temperature. The reaction mixture temperature was slowly raised to 25-30°C and maintained for 18-20 hrs. The reaction mixture was cooled to 10-15°C and P H was adjusted to 2 with cone hydrochloric acid.
  • Example 3 Preparation of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l-yl]butanoic acid (IIB) (3R)-3-(((S)-l-carboxypropylamino)methyl)hexanoic acid (100 g) in acetonitrile (3000 ml) was refluxed for 30 hrs. Activated carbon (10 gm) was added, stirred for 15 min and filtered through hyflow bed.

Landscapes

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

Abstract

La présente invention concerne un procédé de préparation d'intermédiaires d'agents anti-épileptiques. La présente invention concerne en particulier un procédé de préparation d'intermédiaires de brivaracétam. La présente invention concerne un procédé de préparation d'un composé de brivaracétam de formule (I) ou de ses sels comprenant le procédé de préparation de composés intermédiaires.
PCT/IB2020/050391 2019-01-19 2020-01-18 Procédé de préparation d'intermédiaires de brivaracétam et leur utilisation Ceased WO2020148731A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201941002339 2019-01-19
IN201941002339 2019-01-19

Publications (1)

Publication Number Publication Date
WO2020148731A1 true WO2020148731A1 (fr) 2020-07-23

Family

ID=71613287

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2020/050391 Ceased WO2020148731A1 (fr) 2019-01-19 2020-01-18 Procédé de préparation d'intermédiaires de brivaracétam et leur utilisation

Country Status (1)

Country Link
WO (1) WO2020148731A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11673862B2 (en) 2015-05-25 2023-06-13 Suzhou Pengxu Pharmatech Co. Ltd. Processes to produce brivaracetam
EP4282971A1 (fr) 2022-05-23 2023-11-29 Divi's Laboratories Limited Procédé amélioré de préparation de (r)-4-propyl pyrrolidine-2-one, un intermédiaire clé pour la synthèse du brivaracetam
CN117701649A (zh) * 2023-09-08 2024-03-15 山东静远药业有限公司 一种布瓦西坦关键中间体的合成方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016075082A1 (fr) * 2014-11-10 2016-05-19 Sandoz Ag Amination réductrice stéréosélective d'aldéhydes alpha-chiraux au moyen d'ω-transaminases pour la synthèse de précurseurs de la prégabaline et du brivaracétam

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016075082A1 (fr) * 2014-11-10 2016-05-19 Sandoz Ag Amination réductrice stéréosélective d'aldéhydes alpha-chiraux au moyen d'ω-transaminases pour la synthèse de précurseurs de la prégabaline et du brivaracétam

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11673862B2 (en) 2015-05-25 2023-06-13 Suzhou Pengxu Pharmatech Co. Ltd. Processes to produce brivaracetam
US12221413B2 (en) 2015-05-25 2025-02-11 Suzhou Pengxu Pharmatech Co. Ltd. Processes to produce brivaracetam
EP4282971A1 (fr) 2022-05-23 2023-11-29 Divi's Laboratories Limited Procédé amélioré de préparation de (r)-4-propyl pyrrolidine-2-one, un intermédiaire clé pour la synthèse du brivaracetam
US11884623B2 (en) 2022-05-23 2024-01-30 Divi's Laboratories Ltd. Process for the preparation of (R)-4-propyl pyrrolidine-2-one, a key intermediate for synthesis of brivaracetam
CN117701649A (zh) * 2023-09-08 2024-03-15 山东静远药业有限公司 一种布瓦西坦关键中间体的合成方法

Similar Documents

Publication Publication Date Title
CN112135812B (zh) 氯胺酮衍生物及其药物组合物
KR100990949B1 (ko) 클로피도그렐 및 그의 유도체의 제조방법
US8357808B2 (en) Process for producing diamine derivative
US7576234B2 (en) Synthesis of 2-alkyl amino acids
KR100572687B1 (ko) 광학적으로 순수한 4-하이드록시-2-옥소-1-피롤리딘아세트아미드의 제조방법
WO2020148731A1 (fr) Procédé de préparation d'intermédiaires de brivaracétam et leur utilisation
KR102572626B1 (ko) 테트라하이드로퀴놀린 유도체 제조용의 합성 중간체를 제조하기 위한 방법
WO2012025944A2 (fr) Sitagliptine, sels et polymorphes de celle-ci
US20150353577A1 (en) Method for producing (1s,4s,5s)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one
US20080031939A1 (en) Process for the preparation of armodafinil
TWI609017B (zh) 培美曲塞及其離胺酸鹽之製備方法
WO1999002500A1 (fr) Resolution d'amines
US20110257401A1 (en) Process for producing optically active carboxylic acid
EP2397141A1 (fr) Procédé pour la synthèse d'acides aminés beta et leurs dérivés
CA2679741A1 (fr) Nouveaux promedicaments
SI9300286A (sl) Ciklopentan- in -penten-beta-amino kisline
US7612215B2 (en) Process for preparing 2-oxo-1-pyrrolidine derivatives by intramolecular allylation
ES2392207T3 (es) Proceso a partir de ácido shikímico para obtener oseltamivir fosfato
US20160002158A1 (en) Asymmetric synthesis of a substituted pyrrolidine-2-carboxamide
JP5704763B2 (ja) トランス−４−アミノシクロペンタ−２−エン−１−カルボン酸誘導体の製造
US9067868B2 (en) Chemical process for opening ring compounds
US20040122099A1 (en) Process for preparing S-(2-aminoethyl)-2-methyl-L-cysteine
KR20010105381A (ko) 4-시아노-3-히드록시 히드라진, 그 유도체 및 제조방법
WO2016147132A1 (fr) Procédé de préparation de la droxidopa
JP3828197B2 (ja) 光学活性３−（ｐ−メトキシフェニル）グリシッド酸アルカリ金属塩の製造法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20741927

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20741927

Country of ref document: EP

Kind code of ref document: A1