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WO2003092889A1 - Procede de preparation de derives de 2-aminopyrazine - Google Patents

Procede de preparation de derives de 2-aminopyrazine Download PDF

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Publication number
WO2003092889A1
WO2003092889A1 PCT/JP2003/005409 JP0305409W WO03092889A1 WO 2003092889 A1 WO2003092889 A1 WO 2003092889A1 JP 0305409 W JP0305409 W JP 0305409W WO 03092889 A1 WO03092889 A1 WO 03092889A1
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WO
WIPO (PCT)
Prior art keywords
iron
group
acid addition
addition salt
general formula
Prior art date
Application number
PCT/JP2003/005409
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English (en)
Japanese (ja)
Inventor
Takahiro Itoh
Kenji Maeda
Toshiaki Mase
Original Assignee
Banyu Pharmaceutical Co., 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 Banyu Pharmaceutical Co., Ltd. filed Critical Banyu Pharmaceutical Co., Ltd.
Priority to AU2003235951A priority Critical patent/AU2003235951A1/en
Publication of WO2003092889A1 publication Critical patent/WO2003092889A1/fr

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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
    • C07D241/20—Nitrogen atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • B01J27/06—Halogens; Compounds thereof
    • B01J27/128—Halogens; Compounds thereof with iron group metals or platinum group metals

Definitions

  • the present invention is useful in the field of fine chemicals such as pharmaceuticals. More specifically, the present invention relates to a novel method for producing a compound useful as a production intermediate in the field of medicine and the like, and a novel reaction accelerator useful for the production. Background art
  • the 2-aminopyrazine derivative produced by the production method of the present invention can be used, for example, as an intermediate for producing a compound useful as a neuropeptide Y receptor antagonist disclosed in International Patent Publication WO 01/14376, For example, it is useful as an intermediate for the production of luminescent reagents used for the analysis of trace components in living organisms such as peroxides, ATP, calcium ions and steroid hormones (Shimomu raeta 1). (Journal) Vol. 270, pp. 309-312 (1990)).
  • Known methods for producing the pyrazine derivative include, for example, Pharmaceutical Journal Vol. 89, pp. 1646 to 1651 (1969) and Journal of Chemo cal Soc. ociety), p. 932 (1951), but these production methods are not preferable as industrial production methods because the yield of the pyrazine derivative is low.
  • An object of the present invention is to improve the above-mentioned problems of a conventionally known method for producing a 2-aminopyrazine derivative, and to provide an industrially excellent method for producing a 2-aminopyrazine derivative and a reaction accelerator that can be used for the method. .
  • the present inventors have conducted intensive studies on a method for producing a 2-aminopyrazine derivative, and have surprisingly found that an iron compound has a reaction promoting action.
  • the present inventors further have the advantage that the desired 2-aminovirazine derivative of the method of the present invention can be produced in a higher yield than the conventional method, and furthermore, the control of the reaction process is easy, and therefore the present invention is industrially useful.
  • the inventor has found that this is an excellent manufacturing method, and has conducted further studies to complete the present invention.
  • the iron compounds are iron chloride (1 1 1), iron nitrate (1 1 1), iron sulfate (1 1 1), iron bromide (1 1 1), iron ammonium sulfate (1 1 1),
  • the pyrazine ring-forming reaction accelerator according to the above (1) which is iron oxalate (111), iron oxalate (II) or iron fumarate (II),
  • R 1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or aryl group
  • R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, aryl group or halogen atom
  • R 3 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group or an aralkyl group, and an aminoacetonitrile compound or an acid addition salt thereof represented by the following formula: Reacting under the general formula [II]:
  • the iron compounds are iron chloride (1 1 1), iron nitrate (1 1 1), iron sulfate (1 1 1), iron bromide (1 1 1), iron ammonium sulfate (1 1 1), (2) a method for producing a 2-aminopyrazine derivative or an acid addition salt thereof according to the above (3), which is iron (1 1 1), iron (II) oxalate or iron (II) fumarate;
  • Iron compounds include, for example, ferric chloride (111), iron nitrate (111), iron sulfate (II 1), iron bromide (1 I 1), iron ammonium sulfate (II 1) , Ferric citrate (II 1), iron oxalate (II) or iron (II) fumarate, which means a compound containing an iron atom. III) or iron sulfate (III). (II) or (II) attached to the end of the name of each iron compound exemplified as the “iron compound” indicates the oxidation number of the iron atom.
  • alkyl group having 1 to 6 carbon atoms means, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group.
  • a linear or branched alkyl group having 1 to 6 carbon atoms such as a tyl group, sec-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, or isohexyl group.
  • a methyl group, an ethyl group, an n-propyl group, an n-butyl group or an n-hexyl group is preferred.
  • aryl group is, for example, a phenyl group, an O-tolyl group, a P-tolyl group, an m-tolyl group, a 1-naphthyl group, a 2-naphthyl group or an indanyl group having 6 to 1 carbon atoms. It means two aryl groups, among which phenyl, 11-naphthyl or 2-naphthyl is preferred.
  • each group exemplified as the “aryl group” is a normal group that does not inhibit the reaction (for example, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms). You may have it as a substituent.
  • the alkyl group having 1 to 6 carbon atoms has the above-mentioned meaning
  • the cycloalkyl group having 3 to 6 carbon atoms includes, for example, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, and the like.
  • the “aralkyl group” includes, for example, an aryl group having 7 to 12 carbon atoms, such as a benzyl group, a (1-naphthyl) methyl group, a (2-naphthyl) methyl group or a 2-phenylethyl group. Further, each group exemplified as the “aralkyl group” may have a substituent that does not inhibit the above reaction.
  • the “halogen atom” includes, for example, a chlorine atom, a bromine atom, a fluorine atom and an iodine atom.
  • R 1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or aryl group
  • R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, aryl group or halogen atom
  • R 3 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group or an aralkyl group, and an aminoacetonitrile compound or an acid addition salt thereof represented by the following formula: Reacting under the general formula [II]:
  • RR 2 and R 3 have the same meanings as those described above], and then reducing the N-year-old oxide compound or the acid addition salt thereof. It is performed by This method can be carried out industrially advantageously by preferably performing the following processes (1) and (2) successively.
  • (1) To a solvent add a compound represented by the general formula [IV] or an acid addition salt thereof, an aminoacetonitrile compound or an acid addition salt thereof represented by the general formula [III], and an iron compound, and add the compound at about 50 ° C To about 100 ° (: preferably from about 70 ° C to about 100 ° C for about 1 hour to about 36 hours, preferably about 2 hours to about 21 hours, and react with N represented by the general formula [II]. —Produce an oxide compound or an acid addition salt thereof.
  • the amount of the compound represented by the general formula [IV] used in this step is from about 1 equivalent to about 5 equivalents to the aminoacetonitrile compound represented by the general formula [III].
  • aminoacetonitrile compound represented by the general formula [III] is an acid addition salt
  • a base such as N-methylmorpholine, sodium hydroxide, potassium hydroxide, triethylamine, or diisopropylamine is added to the aminoacetonitrile compound.
  • reaction solution containing the N-oxide compound represented by the general formula [II] or the acid addition salt thereof obtained in (1) is transferred to a reduction reaction vessel, and for example, a catalyst such as palladium carbon or platinum carbon is used.
  • a catalyst such as palladium carbon or platinum carbon is used.
  • About 1 mol 1% to about 5 mol% of the aminoaminocetonitrile compound is added, and about 30 to about 10 ° C. under a hydrogen pressure of about 2 to about 6 atm, preferably about 2 to about 5 atm.
  • the reaction is carried out at about 100 ° C, preferably about 30 ° C to about 80, for about 1 hour to about 24 hours, preferably for about 8 hours to about 15 hours.
  • Each of the reactions (1) and (2) of the present invention may be performed in the presence of a solvent.
  • a solvent include water, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, and the like.
  • examples thereof include form-form, tetrahydrofuran, and isopropanol, and a mixed solvent thereof.
  • iron compound used in this step examples include iron chloride (II 1), iron nitrate (I 11), iron sulfate (111), iron bromide (111), and ammonium sulfate (1 11). 11), iron citrate (1 1 1), iron oxalate (II) or iron (II) fumarate
  • the used amount is about 0.5 equivalent to about 1 equivalent based on the aminoacetonitrile compound.
  • the product obtained in the above steps can be obtained by a method known per se, such as column chromatography using silica gel or adsorption resin, liquid chromatography, thin-layer chromatography, solvent extraction or recrystallization / reprecipitation. Purification and isolation can be performed by using a separation and purification method alone or in an appropriate combination as necessary.
  • Examples of the acids in the acid addition salts of the compounds represented by the general formulas [I] to [IV] include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, and organic acids such as oxalic acid and acetic acid. .
  • inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid
  • organic acids such as oxalic acid and acetic acid.
  • Example 1 Example 1
  • aminoacetonitrile hydrochloride 124 g, 1.34 mol
  • methanol 4 L
  • a 12 N aqueous sodium hydroxide solution 123 mL, 1.48 mol
  • isonitrosoacetophenone 100 g, 0.67 mol
  • iron (III) chloride 109 g, 0.67 mol
  • HPLC high-performance liquid chromatography
  • A 0.1% phosphoric acid
  • B acetonitrile
  • Example 2 The compounds of Examples 2 to 7 were produced in the same manner as in the production method of Example 1. However, regarding the purification of the target compound, a silica gel column chromatography (silica gel: Kogel (manufactured by Wako Pure Chemical Industries, Ltd.); ).
  • silica gel column chromatography silica gel: Kogel (manufactured by Wako Pure Chemical Industries, Ltd.); ).
  • the reaction accelerator for a pyrazine ring containing an iron compound as an active ingredient provided by the present invention can improve the yield compared with a conventionally known method for producing a 2-aminopyrazine derivative.
  • a method for producing an aminovirazine derivative can be provided.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé avantageux au plan industriel de préparation de dérivés de aminopyrazine représentés par la formule (I) ou des sels d'addition d'acide de ceux-ci. Dans ladite formule (I), R1 représente hydrogène, alkyle à 1 à 6 atomes de carbone, ou aryle ; R2 représente hydrogène, alkyle à 1 à 6 atomes de carbone, aryle ou halogéno ; et R3 représente hydrogène, alkyle à 1 à 6 atomes de carbone, aryle ou aralkyle. Ledit procédé se caractérise en ce qu'un accélérateur de réaction est utilisé pour la formation du cycle pyrazine qui contient un composé de fer en tant que principe actif.
PCT/JP2003/005409 2002-05-01 2003-04-25 Procede de preparation de derives de 2-aminopyrazine WO2003092889A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003235951A AU2003235951A1 (en) 2002-05-01 2003-04-25 Process for the preparation of 2-aminopyrazine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2002-130136 2002-05-01
JP2002130136A JP2005320249A (ja) 2002-05-01 2002-05-01 ２−アミノピラジン誘導体の製造方法

Publications (1)

Publication Number Publication Date
WO2003092889A1 true WO2003092889A1 (fr) 2003-11-13

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JP (1) JP2005320249A (fr)
AU (1) AU2003235951A1 (fr)
WO (1) WO2003092889A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007041052A2 (fr) 2005-09-29 2007-04-12 Merck & Co., Inc. Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4
WO2008120653A1 (fr) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Dérivé d'indoledione
WO2010051236A1 (fr) 2008-10-30 2010-05-06 Merck Sharp & Dohme Corp. Antagonistes d'isonicotinamide des récepteurs de l'orexine
WO2013059222A1 (fr) 2011-10-19 2013-04-25 Merck Sharp & Dohme Corp. Antagonistes des récepteurs de l'orexine à base de 2-pyrydyloxy-4-nitrile
EP2698157A1 (fr) 2006-09-22 2014-02-19 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de synthèse d'acide gras
WO2020167706A1 (fr) 2019-02-13 2020-08-20 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine 5-alkyl-pyrrolidine
WO2021026047A1 (fr) 2019-08-08 2021-02-11 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type pyrrolidine et pipéridine hétéroaryle
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
WO2022040070A1 (fr) 2020-08-18 2022-02-24 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type bicycloheptane pyrrolidine
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4097478A (en) * 1976-09-20 1978-06-27 Tokai Denka Kogyo Kabushiki Kaisha Process for preparing pyrazines
JPS60169468A (ja) * 1984-02-15 1985-09-02 Koei Chem Co Ltd ピラジン類を製造する方法
US5998618A (en) * 1996-07-11 1999-12-07 Lonza Ag Process for preparing 3-alkoxy-5-alkypyrazin-2-amines
US6066736A (en) * 1997-07-03 2000-05-23 Lonza Ag Process for preparing alkoxypyrazine derivatives
JP2002173486A (ja) * 2000-12-01 2002-06-21 Koei Chem Co Ltd ２，６−ジ置換ピラジンの製造方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4097478A (en) * 1976-09-20 1978-06-27 Tokai Denka Kogyo Kabushiki Kaisha Process for preparing pyrazines
JPS60169468A (ja) * 1984-02-15 1985-09-02 Koei Chem Co Ltd ピラジン類を製造する方法
US5998618A (en) * 1996-07-11 1999-12-07 Lonza Ag Process for preparing 3-alkoxy-5-alkypyrazin-2-amines
US6066736A (en) * 1997-07-03 2000-05-23 Lonza Ag Process for preparing alkoxypyrazine derivatives
JP2002173486A (ja) * 2000-12-01 2002-06-21 Koei Chem Co Ltd ２，６−ジ置換ピラジンの製造方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TAKAHIRO ITOH ET AL.: "Efficient synthesis of substituted 2-aminopyrazines: FeC13-promoted condensation of hydroxyiminoketones with aminoacetonitriles", TETRAHEDRON LETTERS, vol. 43, no. 51, 2002, pages 9287 - 9290, XP004392958 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007041052A2 (fr) 2005-09-29 2007-04-12 Merck & Co., Inc. Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4
EP2698157A1 (fr) 2006-09-22 2014-02-19 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de synthèse d'acide gras
EP2946778A1 (fr) 2006-09-22 2015-11-25 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de la synthèse d'acides gras
WO2008120653A1 (fr) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Dérivé d'indoledione
WO2010051236A1 (fr) 2008-10-30 2010-05-06 Merck Sharp & Dohme Corp. Antagonistes d'isonicotinamide des récepteurs de l'orexine
WO2013059222A1 (fr) 2011-10-19 2013-04-25 Merck Sharp & Dohme Corp. Antagonistes des récepteurs de l'orexine à base de 2-pyrydyloxy-4-nitrile
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
WO2020167706A1 (fr) 2019-02-13 2020-08-20 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine 5-alkyl-pyrrolidine
WO2021026047A1 (fr) 2019-08-08 2021-02-11 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type pyrrolidine et pipéridine hétéroaryle
WO2022040070A1 (fr) 2020-08-18 2022-02-24 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type bicycloheptane pyrrolidine

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JP2005320249A (ja) 2005-11-17

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