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
  • C07D295/023—Preparation; Separation; Stabilisation; Use of additives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems

Definitions

• the present invention relates to a novel method for the synthesis of piperazine and its derivatives of formula 1,
• R is selected from hydrogen or a lower alkyl (lto 6 carbon atoms) group or a phenylalkyl group the alkyl of which has 1 to 4 carbon atoms;
• Ri is selected from hydrogen or a methyl group or a phenyl group optionally substituted with alkyl having 1 to 6 carbon atoms or a phenylalkyl group the alkyl of which has 1 to 4 carbon atoms and R 2 is selected from hydrogen or a methyl group or a fluoromethyl group.
• the compounds of formula 1 of the present invention are useful starting materials for a number of pharmaceutically active compounds like mirtazepine, sparfloxacin, cetirizine, cinnarizine, oxatomide, clozapine and olanzapine.
• Piperazine is generally prepared by treating ammonia with ethylenediamine (SU467073), ammoethylethylenediamine (SU427936), monoethanolamine (CNl 106000) or diethanolamine (JP58035179); or hydrogenation of N-(aminoethyl)ethanolamine (JP49010513).
• ethylenediamine SU467073
• ammoethylethylenediamine SU427936
• monoethanolamine CNl 106000
• diethanolamine JP58035179
• JP49010513 hydrogenation of N-(aminoethyl)ethanolamine
• WO 98/08826 teaches the preparation of 2-arylpiperazines from 2-halopyrazine by reaction with aryl Grignard followed by reduction by hydrogenation in the presence of palladium acetate.
• the Grignard reaction is not facile as it yields 39% product and further requires the use of expensive catalyst viz. [1,2 bis (diphenylphosphino) ethane] nickel (II) chloride in high quantity.
• R 3 is H or a Ci to C 2 alkyl group
• I is H or a Ci to C alkyl group
• R 5 is H or a Ci to C alkyl group
• X is H, F, Cl or Br, atleast one of the symbols R 3 , R*, R 5 and X being different from H.
• WO 98/08826 describes reaction of 2-phenylpiperazine 3 with 3,5- bis(trifluoromethylbenzylbromide) to furnish the corresponding l-alkyl-3 -phenylpiperazine.
• the drawback of this process is that it is carried out at a very low temperature -78°C.
• United States Patent No. 4,772,705 exemplifies preparation of l-methyl-3- phenylpiperazine from 2-phenylpiperazine, using methyl iodide as the methylating agent.
• the yield is low (54%) and the reaction requires low temperature conditions (0°C) for selective alkylation at the 1 -position.
• N-methylpiperazine can be prepared by reacting formaldehyde with aminoethylethanolamine in the presence of hydrogen over a metallic hydrogenation- dehydrogenation catalyst (United States Patent 5,414,087). This requires use of an expensive catalyst like nickel-copper-chrome.
• the principal object of the present invention is to provide a simple and efficient process for preparation of piperazine and its derivatives of aforesaid formula 1
• a further object of the present invention is to provide a simple and efficient process for the preparation of l-alkyl-3 -phenylpiperazine without the need for alkylation of 2- phenylpiperazine and subsequent formation of l-alkyl-2-phenylpiperazine and l,4-dialkyl-2- phenylpiperazine as side products.
• R is selected from hydrogen or a lower alkyl (lto 6 carbon atoms) group or a phenylalkyl group the alkyl of which has 1 to 4 carbon atoms;
• Ri is selected from hydrogen or a methyl group or a phenyl group optionally substituted with alkyl having 1 to 6 carbon atoms or a phenylalkyl group the alkyl of which has 1 to 4 carbon atoms and
• R 2 is selected from hydrogen or a methyl group or a fluoromethyl group, wherein the method comprises the steps: a. reacting esters of formula 11 with substituted or unsubstituted ethylenediamine of formula 7 to give 3,4-dehydropiperazine-2-one and its derivatives of formula 12.
• R, Ri , R 2 are as defined above and R ⁇ is Ci to C 4 linear or branched alkyl group;
• the process of the present invention uses a novel methodology comprising the first step (a) comprising reacting esters of formula 11 with substituted or unsubstituted ethylenediamine of formula 7 to give 3,4-dehydropiperazine-2-one and its derivatives of formula 12, where R, Ri, R 2 , R 3 and R ⁇ are as defined above.
• the starting material of formula 7 is ethylenediamine when R and R 2 are both hydrogen.
• the starting material of formula 7, when R and R 2 are as defined above, may be prepared by reacting alkyl or phenylalkyl amine with 2-chloroethyl amine hydrochloride or its derivatives followed by neutralisation with an alkali.
• step (a) is carried out in the presence of an acid selected from an organic acid, cation exchange resin and mineral acid.
• the organic acid that is preferably employed is an alkyl or an aryl sulphonic acid or a Ci to C 16 carboxylic acid.
• the organic acid is preferably acetic acid.
• cation exchange resins which may be used in step (a) of the process of the present invention are polystyrene-sulfonate resins like lonac C-250H or Amberlite IR-120H, IR-122H or Resintech CG10-H or Dow HCES-H or HGR-H.
• the mineral acid used in step (7) is selected from the group consisting of hydrochloric acid, sulphuric acid, phosphoric acid, perchloric acid or nitric acid.
• step (a) preferably from 0.1 to 10.0 moles of acid is added for 1 mole of substituted or unsubstituted ethylenediamine. More preferably 0.5 to 2.0 moles of acid are added for 1 mole of substituted or unsubstituted ethylenediamine.
• the reaction between monoalkyl ethylenediamine of formula 7 and esters of formula 11 may be preferably carried out in an inert solvent in which the reactants are soluble.
• solvents that can be employed are Ci to C 6 alcohols such as ethanol and propanols, hydrocarbons such as toluene, xylenes, benzene and methylene chloride.
• the most preferred solvents are alkanols and aromatic hydrocarbons ' with boiling range between 60 to 120 ° C.
• the reaction is carried out at reaction temperatures of 60 to 120 ° C.
• esters of formula 11 required for the above reaction include those wherein, the alkyl residue is Ci to C 6 alkyls which are linear, branched or cyclic alkyls, the preferred ones being Ci to C alkyls like methyl, ethyl, isopropyl, cyclopropyl and tertiarybutyl and the most preferred being methyl and ethyl.
• step (B) Reduction of compounds of formula 12 to piperazine its derivatives of formula 1.
• step (b) 3,4-dehydro-piperazine-2-one and its derivatives of formula 12 is reacted with a reducing agent to yield piperazine and its derivatives 1.
• Reducing agent that may be used is selected from lithium aluminium hydride (LAH), sodium borohydride, aluminium hydride, potassium borohydride or borane using standard conditions to produce piperazine and its derivatives 1.
• These compound of formula 17 is preferably prepared by the steps comprising (a) Reacting l-methyl-3 -phenylpiperazine with 2-chloro-3-cyanopyridine of formula 13 to give l-(3-cyanopyridyl - 2-)-4-methyl-2-phenyl ⁇ iperazine of formula 14;
• Reduction of the compound of formula 15 to the compound of formula 16 may be effected with a reducing agent like metal hydride selected from lithium aluminium hydride, sodium borohydride, aluminium hydride, potassium borohydride and diborane or by means of catalytic hydrogenation.
• a reducing agent like metal hydride selected from lithium aluminium hydride, sodium borohydride, aluminium hydride, potassium borohydride and diborane or by means of catalytic hydrogenation.
• the step of cyclisation may be carried out under strongly dehydrating conditions like elevated temperature or by addition of an acid selected from sulphuric acid, concentrated hydrochloric acid, picric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid (PPA), phosphorous oxychloride, phosphorous trioxide, phosphorous pentoxide and lewis acids like aluminium chloride, ferric chloride, zinc chloride, tin chloride, titanium chloride, boron trifluoride, antimony pentachloride and zirconium tetrachloride.
• an acid selected from sulphuric acid, concentrated hydrochloric acid, picric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid (PPA), phosphorous oxychloride, phosphorous trioxide, phosphorous pentoxide and lewis acids like aluminium chloride, ferric chloride, zinc chloride, tin chloride, titanium chloride, boron trifluoride, anti
• Piperazine and its derivatives of formula 1 are useful intermediates for a number of pharmaceutically active compounds like antidepressant mirtazepine, antibacterial sparfloxacin, antihistamines like cetirizine, cinnarizine, oxatomide and antipsychotics like clozapine, olanzapine.
• LAH Lithium aluminium hydride

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Priority Applications (2)

Applications Claiming Priority (2)

Publications (1)

Family

ID=11097306

Family Applications (1)

Country Status (6)

Cited By (1)

Citations (1)

Family Cites Families (10)

• 2000
  • 2000-11-07 IN IN994MU2000 patent/IN190478B/en unknown
• 2001
  • 2001-06-29 WO PCT/IN2001/000129 patent/WO2002038552A1/en not_active Ceased
  • 2001-06-29 AU AU2001278669A patent/AU2001278669A1/en not_active Abandoned
  • 2001-07-27 BE BE2001/0513A patent/BE1013317A6/fr not_active IP Right Cessation
  • 2001-08-02 CH CH01428/01A patent/CH692342A5/de not_active IP Right Cessation
  • 2001-10-25 US US10/037,309 patent/US6603003B2/en not_active Expired - Fee Related

Patent Citations (1)

Non-Patent Citations (6)

Also Published As

Similar Documents

Legal Events