WO2018002696A1 - Processus amélioré pour la préparation d'un agent antihistaminique - Google Patents

Processus amélioré pour la préparation d'un agent antihistaminique Download PDF

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Publication number
WO2018002696A1
WO2018002696A1 PCT/IB2016/054885 IB2016054885W WO2018002696A1 WO 2018002696 A1 WO2018002696 A1 WO 2018002696A1 IB 2016054885 W IB2016054885 W IB 2016054885W WO 2018002696 A1 WO2018002696 A1 WO 2018002696A1
Authority
WO
WIPO (PCT)
Prior art keywords
cyclizine
improved process
preparation
formaldehyde
formula
Prior art date
Application number
PCT/IB2016/054885
Other languages
English (en)
Inventor
Srinivasan Shanmugam
Laxma Reddy GOUNI
Gowri Naidu Tammireddy
Madduleti TOGATA
Original Assignee
Fleming Laboratories 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 Fleming Laboratories Limited filed Critical Fleming Laboratories Limited
Publication of WO2018002696A1 publication Critical patent/WO2018002696A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms

Definitions

  • the present invention relates to an improved process for the preparation of an antihistamine agent.
  • the present invention particularly relates to an improved process for the preparation of Cyclizine or its salts.
  • the present invention more particularly relates to an improved process for the preparation of Cyclizine hydrochloride.
  • the present invention further relates to commercially feasible process for the preparation of Cyclizine hydrochloride.
  • Cyclizine is a piperazine-derivative. It is used for the prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness, and vertigo. Cyclizine has also been found to inhibit cytochrome P450 CYP2D6, an important liver enzyme. Cyclizine is metabolised to its N-demethylated derivative, norcyclizine, which has little antihistaminic (HI) activity compared to Cyclizine.
  • HI antihistaminic
  • Cyclizine is an orally or parenterally administered histamine HI receptor antagonist.
  • the chemical name of Cyclizine is N-benzhydryl-N'-methylpiperazine and the molecular formula is C18H22N2 with molecular
  • the structural formula is:
  • Cyclizine is first disclosed in US 2,630,435 A. This patent discloses a process for the preparation of Cyclizine dihydrochloride. The process involves the condensation reaction of benzhydryl chloride with N-methyl piperazine, followed by treating with hydrochloric acid to form Cyclizine dihydrochloride. The process is shown in the scheme given below:
  • BE539693 Al discloses a process for preparing Cyclizine, which is depicted in the scheme given below:
  • BE539693 Al also discloses an alternate process for preparing Cyclizine, which is shown in the scheme given below:
  • the present inventors have surprisingly found an improved process for preparing Cyclizine which involves methylating DPMP (benzhydryl piperazine) using Eschweiler- Clarke reaction methodology, wherein the developed process has less number of steps, more industrially scalable with high yields.
  • the main objective of the present invention is to provide an improved process for the preparation of an antihistamine agent.
  • the present invention provides an improved process for the preparation of Cyclizine
  • the present invention provides an improved process for the preparation of Cyclizine
  • the present invention provides an improved process for the preparation of Cyclizine
  • the present invention provides an improved process for the preparation of Cyclizine hydrochlori
  • the present invention provides an improved process for the preparation of Cyclizine,
  • the present invention provides an improved process for preparing Cyclizine or its salts which is economically viable.
  • the present invention provides an improved process for preparing Cyclizine free base using Eschweiler-Clarke reaction methodology.
  • the developed process using Eschweiler-Clarke reaction methodology is commercially feasible, does not involve any side reactions, and contains fewer impurities.
  • Eschweiler-Clarke reaction which is also called as Eschweiler-Clarke methylation is widely used for the methylation of primary or secondary amines. Methylation using Eschweiler-Clarke reaction will not produce quaternary ammonium salts, but instead will stop at the tertiary amine stage.
  • the present invention provides an improved process for preparing Cyclizine which comprises methylating amine of Formula I i.e DPMP (benzhydryl piperazine) with formaldehyde to give imine derivative of compound of Formula I.
  • the imine derivative of Formula I is reduced using an acid which acts as a source of hydride to give Cyclizine free base.
  • the acid used in the present invention is selected from an acid which acts as a source of hydride.
  • the acid is selected from oxalic acid and its hydrates, formic acid. Preferably formic acid.
  • the present invention provides an improved process for preparing Cyclizine hydrochloride which comprises methylating amine of Formula I i.e DPMP (benzhydryl piperazine) with formaldehyde to give imine derivative of compound of Formula I.
  • DPMP benzhydryl piperazine
  • the imine derivative of Formula I is reduced using formic acid which acts as a source of hydride to give Cyclizine free base, followed by treating it with hydrochloric acid in the presence of a suitable solvent to give Cyclizine HC1.
  • the first methylation of the amine begins with imine formation with formaldehyde.
  • the formic acid acts as a source of hydride and reduces the imine to a secondary amine.
  • the driving force is the formation of carbon dioxide gas.
  • Formation of the tertiary amine is similar. From this mechanism it is clear that a quaternary ammonium salt will never form, because it is impossible for a tertiary amine to form another imine or iminium ion.
  • the present invention provides solvent free methylation of compound of Formula I to give Cyclizine free base, wherein water alone is used in the reaction which makes the process more economical and environmental friendly.
  • the developed process is simple and does not involve any complicated reagents.
  • the yield of the product is very high which is commercially feasible.
  • the present invention provides the methylation of compound of Formula I to give Cyclizine free base in water medium to emphasize Green approach, unique, aqueous medium which is non-toxic liquid, sustainable chemistry.
  • the present invention provides an improved process for the preparation of Cyclizine
  • the present invention provides an improved process for the preparation of Cyclizine
  • the present invention provides an improved process for the preparation of Cyclizine
  • the present invention provides an improved process for the preparation of Cyclizine
  • the present invention provides an improved process for the preparation of Cycliz
  • the present invention provides an improved process for the preparation of Cyclizine hydrochloride
  • Salts derived from organic acids such as aliphatic mono and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used.
  • 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,
  • solvent as defined in the presence invention is 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-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents” such as acetonitrile

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

Abstract

La présente invention concerne un procédé amélioré pour la préparation d'un agent antihistaminique. La présente invention concerne un procédé amélioré pour la préparation de Cyclizine ou ses sels. La présente invention concerne plus particulièrement un procédé amélioré pour la préparation de Cyclizine hydrochloride. La présente invention concerne en outre un procédé commercialement faisable pour la préparation de Cyclizine hydrochloride.
PCT/IB2016/054885 2016-06-27 2016-08-13 Processus amélioré pour la préparation d'un agent antihistaminique WO2018002696A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ININ201641021910 2016-06-27
IN201641021910 2016-06-27

Publications (1)

Publication Number Publication Date
WO2018002696A1 true WO2018002696A1 (fr) 2018-01-04

Family

ID=60784926

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2016/054885 WO2018002696A1 (fr) 2016-06-27 2016-08-13 Processus amélioré pour la préparation d'un agent antihistaminique

Country Status (1)

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WO (1) WO2018002696A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE539693A (fr) * 1955-07-08 1955-07-30 P A J Janssen Procédé d'obtention de methylpiperazines substutees

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE539693A (fr) * 1955-07-08 1955-07-30 P A J Janssen Procédé d'obtention de methylpiperazines substutees

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
STANLEY H. PINE ET AL.: "The Formic Acid-Formaldehyde Methylation of Amines", J . ORG. CHEM., vol. 36, no. 6, 1971, pages 829 - 832, XP003027423 *

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