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WO1997007106A1 - Nouveau procede de preparation des derives de la piperazine n-monosubstituee - Google Patents

Nouveau procede de preparation des derives de la piperazine n-monosubstituee Download PDF

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Publication number
WO1997007106A1
WO1997007106A1 PCT/SE1996/000977 SE9600977W WO9707106A1 WO 1997007106 A1 WO1997007106 A1 WO 1997007106A1 SE 9600977 W SE9600977 W SE 9600977W WO 9707106 A1 WO9707106 A1 WO 9707106A1
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WO
WIPO (PCT)
Prior art keywords
process according
alkyl
formula
compound
ethyl
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/SE1996/000977
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English (en)
Inventor
Yevgeni Besidski
Alf Claesson
Kristina Luthman
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.)
AstraZeneca AB
Original Assignee
Astra AB
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 Astra AB filed Critical Astra AB
Priority to EP96925241A priority Critical patent/EP0846106A2/fr
Priority to AU65397/96A priority patent/AU6539796A/en
Publication of WO1997007106A1 publication Critical patent/WO1997007106A1/fr
Priority to NO980607A priority patent/NO980607L/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention is directed to a new process for the selective preparation of piperazine derivatives.
  • the piperazine nucleus is a constituent of many pharmaceutically useful compounds. Most of these compounds contain different substituents on one or both of the two nitrogens. A problem in the synthesis of these compounds relates to the differentiation of the two nitrogens in the synthesis sequence, such that selective derivatives of each can be made.
  • the present invention is directed to a new process for the selective preparation of piperazine derivatives that are monosubstituted in the 2-position or are disubstituted at carbons 2 and 5, and which additionally, have a single substituent at one of the nitrogens or have two different nitrogen substituents.
  • One aspect of the invention relates to the selective formation of N-protected esters or amides of PZC, of the general formula I
  • R is a straight, branched or cyclic C1-C20 alkyl group, or an arylalkyl wherein aryl is
  • phenyl or substituted phenyl and alkyl is _-C(. alkyl;
  • R is defined as for R , or is benzyl, hydroxyalkyl, or an aminoalkyl group wherein alkyl is
  • Y is OH, a group OR , wherein R 1 is as defined above, or NR 3 R 4 ,wherein R 3 and R 4 independently are hydrogen, C1-C20 alkyl, or aralkyl, wherein aryl is phenyl or substituted
  • phenyl and alkyl is C2-C6 alkyl.
  • R and R are each and independently C1-C20 alkyl, and Y is OR wherein R is
  • the process for the selective formation of the compounds I comprises the following steps:
  • R 2 and Y are as defined above and which is readily available either commercially or by methods known to one skilled in the art (see e.g. Barlin, G.B. (ed.) The Pyrazines, 1982, Wiley-Intersci., N.Y.) is hydrogenated in the presence of a catalyst and at least one equivalent of a C1-C20 alkoxycarbonyl-donating reagent, which is compatible with hydrogenation conditions, e.g. di-tert-butyldicarbonate, in an inert solvent compatible with hydrogenation conditions, and at temperatures and pressures commonly employed in such processes , giving the hitherto unknown N-l protected tetrahydropyrazinederivatives of the formula HI
  • R 1 , R 2 and Y are as defined above, in good yields
  • the compound of the formula HI is isolated by conventional laboratory techniques known to one skilled in the art, purified by silica gel chromatography or other well-known techniques known to a person skilled in the art, e.g. recrystallization, and further converted or, after removal of the solvents and the excessive alkoxycarbonyl-donating reagent, e.g. by reacting with 2-aminoethanol and then filtering through a pad of silica gel, directly used as the reactant in step iii; and
  • the catalyst for the hydrogenation in step i) can be selected from a wide variety of transition metals, preferably from the platinum metals.
  • the catalyst can be used as such, or can be supported on carbon, silica, aluminia or other inert materials known to the man skilled in the art, or can be a transition metal which is solubilized by means of organic ligands, e.g. phosphine ligands such as triphenylphosphine.
  • organic ligands e.g. phosphine ligands such as triphenylphosphine.
  • the alkoxycarbonyl-donating reagent in step i) is preferably in the form of an anhydride of a monoester of carbonic acid, for example di-tert-butyl- dicarbonate or dimethyl dicarbonate.
  • the inert solvent in step i) can be chosen among a great variety of inert solvents known to the man skilled in the art.
  • inert solvents that can be used are ethyl acetate, tetrahydrofuran, dioxane, toluene, dimethylformamide, ethylmethylketone and diisopropylether.
  • Reaction temperatures may vary from room temperature to just below the boiling point of the solvent, and the pressure may vary from atmospheric pressure to 200 bar, both parameters depending on the reactivities of the catalyst and the substrate.
  • Particularly preferred conditions *or obtaining the compounds of the formula HI by hydrogenation of a pyrazine involve the use of a palladium catalyst, e.g. 5% Pd on charcoal, in amounts ranging from 0.5-30 mol in an inert solvent, preferably ethyl acetate, at room temperature and at a hydrogen pressure of 1-5 bar, in the presence of 1.1-1.5 equivalents of di-tert-butyl dicarbonate.
  • a palladium catalyst e.g. 5% Pd on charcoal
  • Preferred conditions for isolating a compound of the formula ELI in step ii) involve removal of the catalyst by filtration through an inert adsorbent , e.g. Celite or silica gel, concentrating the mixture in vacuo and initiating crystallization of a compound of the formula DI.
  • the product may be purified by recrystallization.
  • step iii) for the conversion of a compound of the formula DI into a compound of the formula I can be performed by a variety of possibilities regarding reagents and conditions.
  • One preferred reaction is hydrogenation in the presence of a transition metal catalyst chosen among the platinum metals known to catalyze addition of hydrogen over a double bond, in a suitable solvent, for example glacial acetic acid, ethyl acetate, tetrahydrofuran, dioxan, 2-propanol, toluene, and at a pressure ranging from atmospheric to 200 bar, and at a temperature ranging from room temperature to just below the boiling point of the solvent
  • Another equally preferred reaction is reduction using a hydride reagent that is known to add hydrogen to double bonds.
  • One particularly preferred reagent in the latter category is sodium cyanoborohydride in a weakly acidic solvent, for example acetic acid, or, when the group R 1 is not affected by strong acids, in diethyl ether in the presence of hydrochloric acid.
  • Still another equally preferred reagent is a metal which transfers an electron to the double bond creating a radical anion which then reacts further to give overall addition of hydrogen.
  • Preferred conditions for such reactions are the use of magnesium in methanol or lithium in 2-propanol. Conditions can be chosen so that a cis- or trans-isomer is formed predominantly.
  • Preferred conditions for obtaining the cis-isomer is catalytic hydrogenation.
  • Particularly preferred conditions for hydrogenation of the double bond of a compound of the formula HI involve the use of a palladium catalyst in amounts ranging from 0.1-20 mol% in glacial acetic acid at room temperature and at a pressure of 3-5 bar.
  • the process according to the present invention provides an economical and convenient synthetic route to a wide variety of N-monoprotected 1, 4, 5, 6-tetrahydropyrazine derivatives and thereby to the corresponding monoprotected piperazine derivatives which in tum can be converted to a whole range of other compounds.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un nouveau procédé permettant la préparation sélective d'un composé de formule (I) où R1 est un groupe alkyle à chaîne droite, ramifiée ou cyclique, ou un arylalkyle où l'aryle est un C¿6?-aryle et l'alkyle un C2-C6 alkyle; R?2¿ est défini de la même manière que R1, ou est benzyle, hydroxy, ou un groupe aminoalkyle où l'alkyle est un C¿1?-C20 alkyle à chaîne droite, ramifiée ou cyclique; Y est OH, un groupe OR?1¿ tel que défini ci-dessus, ou NR?3R4 où R3 et R4¿ sont indépendamment l'un de l'autre l'hydrogène, C¿1?-C20 alkyle, ou aralkyle où l'aryle est un C6-aryle et l'alkyle un C2-C6 alkyle. Elle concerne également les produits obtenus par ledit procédé et les intermédiaires utilisés au cours du procédé.
PCT/SE1996/000977 1995-08-18 1996-07-29 Nouveau procede de preparation des derives de la piperazine n-monosubstituee Ceased WO1997007106A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP96925241A EP0846106A2 (fr) 1995-08-18 1996-07-29 Nouveau procede de preparation des derives de la piperazine n-monosubstituee
AU65397/96A AU6539796A (en) 1995-08-18 1996-07-29 New process for the preparation of n-monosubstituted piperazin derivatives
NO980607A NO980607L (no) 1995-08-18 1998-02-12 Ny fremgangsmåte for fremstilling av N-monosubstituerte piperazinderivater

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9502876A SE9502876D0 (sv) 1995-08-18 1995-08-18 New process
SE9502876-7 1995-08-18

Publications (1)

Publication Number Publication Date
WO1997007106A1 true WO1997007106A1 (fr) 1997-02-27

Family

ID=20399215

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1996/000977 Ceased WO1997007106A1 (fr) 1995-08-18 1996-07-29 Nouveau procede de preparation des derives de la piperazine n-monosubstituee

Country Status (6)

Country Link
EP (1) EP0846106A2 (fr)
AU (1) AU6539796A (fr)
CA (1) CA2228896A1 (fr)
NO (1) NO980607L (fr)
SE (1) SE9502876D0 (fr)
WO (1) WO1997007106A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0368670A1 (fr) * 1988-11-11 1990-05-16 Takeda Chemical Industries, Ltd. Composés pipéraziniques trisubstitués, leur préparation et leur application

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0368670A1 (fr) * 1988-11-11 1990-05-16 Takeda Chemical Industries, Ltd. Composés pipéraziniques trisubstitués, leur préparation et leur application

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
TETRAHEDRON LETTERS, Volume 30, No. 39, 1989, CHRISTOPHER F. BIGGE et al., "New Preparations of the N-Methyl-D-Aspartate Receptor Antagonist, 4-(3-Phosphonopropyl)-2-Piperazinecarboxyli c Acid (CPP)", pages 5193-5196. *
TETRAHEDRON LETTERS, Volume 36, No. 36, 1995, K. ROSSEN et al., "Asymmetric Hydrogenation of Tetrahydropyrazines: Synthesis of (S)-Piperazine-2-tert-butylcarboxamide, an Intermediate in the Preparation of the HIV Protease Inhibitor Indinavir", pages 6419-6422. *

Also Published As

Publication number Publication date
NO980607D0 (no) 1998-02-12
SE9502876D0 (sv) 1995-08-18
EP0846106A2 (fr) 1998-06-10
CA2228896A1 (fr) 1997-02-27
AU6539796A (en) 1997-03-12
NO980607L (no) 1998-02-12

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