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WO2018154597A1 - Procédé de synthèse de bromure de glycopyrronium - Google Patents

Procédé de synthèse de bromure de glycopyrronium Download PDF

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Publication number
WO2018154597A1
WO2018154597A1 PCT/IN2018/050083 IN2018050083W WO2018154597A1 WO 2018154597 A1 WO2018154597 A1 WO 2018154597A1 IN 2018050083 W IN2018050083 W IN 2018050083W WO 2018154597 A1 WO2018154597 A1 WO 2018154597A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
equiv
methyl
glycopyrronium bromide
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/IN2018/050083
Other languages
English (en)
Inventor
G. Nithun REDDY
G. Samhitha REDDY
G. Madaalasa REDDY
M Ramani
G. Pratap REDDY
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.)
GbR Laboratories Pvt Ltd
Rachana Pharma Tech
Original Assignee
GbR Laboratories Pvt Ltd
Rachana Pharma Tech
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 GbR Laboratories Pvt Ltd, Rachana Pharma Tech filed Critical GbR Laboratories Pvt Ltd
Publication of WO2018154597A1 publication Critical patent/WO2018154597A1/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
    • C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—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 no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/12—Oxygen or sulfur atoms

Definitions

  • Glycopyrronium bromide (or glycopyrrolate) is a quaternary ammonium salt with the following chemical name: 3[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethyl pyrrolidinium bromide.
  • the structural formula is shown below
  • the compound is an anticholinergic agent which is formulated for intramuscular or intravenous injection.
  • Glycopyrronium bromide is indicated for use as a preoperative anti muscarinic to reduce salivary, tracheobronchial, and pharyngeal secretions; to reduce the volume and free acidity of gastric secretions; and to block cardiac vagal inhibitory reflexes during induction of anesthesia and/or intubation. When indicated, it is used intraoperatively to counteract surgically or drug induced or vagal reflexes associated arrhythmias.
  • Glycopyrrolate protects against the peripheral muscarinic effects (e.g., bradycardia and excessive secretions) of cholinergic agents such as neostigmine and pyridostigmine given to reverse the neuromuscular blockade due to non-depolarizing muscle relaxants.
  • cholinergic agents such as neostigmine and pyridostigmine
  • glycopyrronium bromide comprising, in a first step, a reaction of N-methyl pyrrol idin-3-ol with a compound of Formula I or Formula II as described herein followed by a coupling reaction with a suitable organo- magnesium reagent as described herein.
  • glycopyrronium bromide Previously known methods for synthesis of glycopyrronium bromide comprised a reaction of alpha-cycl openty I phenyl acetyl chloride with N-methyl pyrrol idin-3-ol.
  • described herein are processes wherein the synthesis of glycopyrronium bromide is achieved by initially coupling N-methyl pyrrol idin-3-ol with either 2-oxo-2-phenyl acetic acid derivatives or 2-oxo-2- cyclopentyl acetic acid derivatives followed by a Grignard reaction, as described in more detail i n the E xampl es secti on.
  • a process for preparation of glycopyrronium bromide comprising
  • X is H, OH, OMe or CI
  • Scheme 1 describes certain non- limiting reaction conditions for the reaction of a compound of Formula I with N- methyl pyrrol i din- 3-ol.
  • Other suitable coupling protocols will be apparent to one of ski 11 i n the art and are contempi ated wi thi n the scope of embodi ments descri bed herei n.
  • said process further comprises reacting the compound of structure 5 with methyl bromide to obtain a compound of structure 6
  • glycopyrroni urn bromide comprising
  • Y is H, OH, OMe or CI
  • Scheme 2 describes certain non- limiting reaction conditions for the reaction of a compound of Formula II with N-methylpyrrolidin-3-ol.
  • Other suitable coupling protocols will be apparent to one of skill in the art and are contemplated within the scope of embodiments described herein.
  • the process described above further comprises reacting the compound of structure 5 with methyl bromide to obtain a compound of structure 6
  • the product 3A is also obtained by reaction of 2 with other reagents, phenyl oxalic acid, methyl phenyl oxalate, and phenyl hemi-oxaldehyde respectively as shown in Scheme 1.
  • the product 3B is also obtained by reaction of 2 with other reagents, phenyl oxalic acid, methyl phenyl oxalate, and phenyl hemi-oxaldehyde respectively as shown in Scheme 2.

Landscapes

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

Abstract

La présente invention concerne des procédés de préparation de bromure de glycopyrronium comprenant la réaction de N-méthylpyrrolidin-3-ol avec des composés de formule I ou de formule II suivie par des étapes supplémentaires.
PCT/IN2018/050083 2017-02-22 2018-02-19 Procédé de synthèse de bromure de glycopyrronium Ceased WO2018154597A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201741006245 2017-02-22
IN201741006245 2017-02-22

Publications (1)

Publication Number Publication Date
WO2018154597A1 true WO2018154597A1 (fr) 2018-08-30

Family

ID=63254184

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2018/050083 Ceased WO2018154597A1 (fr) 2017-02-22 2018-02-19 Procédé de synthèse de bromure de glycopyrronium

Country Status (1)

Country Link
WO (1) WO2018154597A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113861030A (zh) * 2020-06-30 2021-12-31 天津药业研究院股份有限公司 格隆溴铵中间体及其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2956062A (en) * 1959-02-26 1960-10-11 Robins Co Inc A H Esters of amino alcohols
US20090005577A1 (en) * 2007-06-29 2009-01-01 Nikolai Kraiouchkine Method of producing 1-substituted 3-pyrrolates
CN103159659A (zh) * 2011-12-19 2013-06-19 沈阳药科大学 一种毒蕈碱受体拮抗剂格隆溴铵的制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2956062A (en) * 1959-02-26 1960-10-11 Robins Co Inc A H Esters of amino alcohols
US20090005577A1 (en) * 2007-06-29 2009-01-01 Nikolai Kraiouchkine Method of producing 1-substituted 3-pyrrolates
CN103159659A (zh) * 2011-12-19 2013-06-19 沈阳药科大学 一种毒蕈碱受体拮抗剂格隆溴铵的制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113861030A (zh) * 2020-06-30 2021-12-31 天津药业研究院股份有限公司 格隆溴铵中间体及其制备方法和应用

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