WO2010098332A1 - Procédé de production de composés polycycliques et de leurs intermédiaires - Google Patents

Procédé de production de composés polycycliques et de leurs intermédiaires Download PDF

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Publication number
WO2010098332A1
WO2010098332A1 PCT/JP2010/052808 JP2010052808W WO2010098332A1 WO 2010098332 A1 WO2010098332 A1 WO 2010098332A1 JP 2010052808 W JP2010052808 W JP 2010052808W WO 2010098332 A1 WO2010098332 A1 WO 2010098332A1
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Prior art keywords
salt
formula
compound
compound represented
following formula
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PCT/JP2010/052808
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English (en)
Japanese (ja)
Inventor
厚 鎌田
健雄 佐々木
敏之 上村
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エーザイ・アール・アンド・ディー・マネジメント株式会社
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Publication of WO2010098332A1 publication Critical patent/WO2010098332A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/30—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C243/32—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • 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
    • C07D471/02—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 two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a method for producing a polycyclic compound and an intermediate thereof. More specifically, the present invention is a compound useful as an A ⁇ production inhibitor effective for the treatment of neurodegenerative diseases such as Alzheimer's disease and Down's syndrome caused by amyloid beta (hereinafter referred to as A ⁇ ), (8S) -2 - ⁇ (E) -2- [6-Methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridin-2-yl] vinyl ⁇ -8- [2- (trifluoromethyl) phenyl]-
  • a ⁇ amyloid beta
  • the present invention relates to a process for producing 5,6,7,8-tetrahydro [1,2,4] triazolo [1,5-
  • Patent Document 1 includes the following formula: [In the formula, U represents a nitrogen atom, V represents an oxygen atom, G represents an oxygen atom, R 1 represents a hydrogen atom, a halogen atom, etc., R 2 represents a hydrogen atom, an alkyl group, etc. R 5 represents an alkyl group or the like, R 7 represents an alkyl group or the like, R 8 represents a halogen atom or the like, R 9 represents an alkyl group or the like, and R 10 represents an alkyl group or the like]
  • U represents a nitrogen atom
  • V represents an oxygen atom
  • G represents an oxygen atom
  • R 1 represents a hydrogen atom, a halogen atom, etc.
  • R 2 represents a hydrogen atom, an alkyl group, etc.
  • R 5 represents an alkyl group or the like
  • R 7 represents an alkyl group or the like
  • R 8 represents a halogen atom or the like
  • R 9 represents an alkyl group or the like
  • Patent Document 2 includes the following formula: [Wherein Ar 1 represents an imidazolyl group or the like which may be substituted with a C1-6 alkyl group, Ar 2 represents a phenyl group or the like which may be substituted with a C1-6 alkoxy group, and X 1 represents A compound represented by the formula [1] represents a double bond or the like, and Het represents an imidazolyl group or the like which may be substituted with a C1-6 alkyl group or the like] is capable of suppressing the production of amyloid beta 40 and 42 from amyloid precursor protein. , And methods for producing the compounds.
  • Patent Document 3 discloses the following formula: [Wherein R 1 and R 2 represent a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group or the like, and Het represents a 5- or 6-membered unsaturated heterocyclic group or the like] That the compound represented by the formula shows an A ⁇ production inhibitory action, and a method for producing these compounds is disclosed.
  • an object of the present invention is to provide an industrially sufficiently advantageous production method of a compound of the formula (I) or a salt thereof and an intermediate used for the production thereof.
  • the present inventors have found the present invention as a result of intensive studies aimed at solving the above problems. That is, the present invention (1)
  • the following formula (II) [Wherein X represents a halogen atom] or a salt thereof, and the following formula (III)
  • the following formula (IV) Is subjected to a Sandmeyer reaction to give a compound represented by the following formula (II): [Wherein X represents a halogen atom] or a salt thereof, and further a compound represented by formula (II) or a salt thereof; And
  • (8S) -2- ⁇ (E) -2- [6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridin-2- is useful as an A ⁇ production inhibitor.
  • Yl] vinyl ⁇ -8- [2- (trifluoromethyl) phenyl] -5,6,7,8- [1,2,4] triazolo [1,5-a] pyridine or a salt thereof industrially advantageous Can be manufactured.
  • a novel synthetic intermediate useful for this purpose can be provided.
  • the compound represented by formula (I) may be referred to as compound (I).
  • the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a bromine atom or an iodine atom.
  • the leaving group means a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a chlorine atom or a bromine atom.
  • the coupling reaction in the present invention (Step 1 in the above reaction scheme) is usually performed in the presence of a palladium catalyst and a base (for example, RF Heck, “Org. Reactions”, 1982, Vol. 27, p. 345). See).
  • compound (III) is usually used in an amount of 0.7 to 1.5 equivalents, preferably 0.8 to 1.2 equivalents, relative to compound (II).
  • the palladium catalyst a zero-valent or divalent palladium compound is used.
  • the zero-valent palladium compound tris (dibenzylideneacetone) dipalladium (0) is preferable, and as the divalent palladium compound, palladium (II) acetate is preferable. Used.
  • a trivalent phosphine compound is also used as a ligand.
  • tris (dibenzylideneacetone) dipalladium (0) is used as the palladium compound
  • tri (ortho-tolyl) phosphine is used as the ligand.
  • the palladium catalyst is used in an amount of 0.001 to 0.5 equivalent, preferably 0.005 to 0.2 equivalent, as palladium, relative to compound (II).
  • an organic base such as triethylamine or diisopropylethylamine, or an inorganic base such as potassium carbonate is usually used, and diisopropylethylamine is preferably used.
  • the amount of the base used is 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound (II).
  • a reaction solvent may or may not be used, but when used, there is no particular limitation as long as the reaction is not inhibited, and N, N-dimethylformamide is preferably used.
  • the reaction temperature is room temperature to the boiling point of the solvent, preferably 50 to 150 ° C, more preferably 80 to 120 ° C. This reaction can also be preferably carried out in an inert gas atmosphere such as nitrogen or argon. Under preferable reaction conditions, the reaction is completed in 1 to 24 hours.
  • the compound of formula (IV) is usually made into a diazonium compound using a nitrite such as sodium nitrite and an acid, and then the diazonium compound and a halogen are used. It can be performed by reacting with copper chloride. Alternatively, the reaction is carried out by reacting the compound of formula (IV) with a nitrite in the presence of copper halide, in the presence or absence of methylene halide.
  • the compound of formula (IV) is reacted with a nitrite such as sodium nitrite in the presence of an acid in an aqueous solvent to form a diazonium compound, and the resulting diazonium compound and copper halide are usually not isolated. It can be performed by reacting.
  • a nitrite such as sodium nitrite
  • hydrohalic acid is usually used in an amount of 1.5 to 3 equivalents, preferably 1.8 to 2.2 equivalents, relative to the compound of formula (IV).
  • sodium nitrite or potassium nitrite is usually used in an amount of 0.8 to 1.2 equivalents, preferably 0.9 to 1.1 equivalents, relative to the compound of formula (IV).
  • the copper halide to be used 1 to 10 equivalents, preferably 2 to 5 equivalents, of copper dibromide or cuprous iodide are used.
  • the halogenation reaction is bromination, hydrobromic acid is used as an acid together with copper dibromide.
  • hydroiodic acid is used as an acid together with cuprous iodide.
  • the reaction is usually carried out by adding a diazonium compound while stirring the copper halide in an aqueous solvent containing no solvent or water or 1 to 10 equivalents of a hydrogen halide with respect to the compound of formula (IV).
  • the reaction for obtaining the diazonium compound is usually carried out at ⁇ 10 to 0 ° C., and the halogenation reaction is usually carried out at 20 to 100 ° C. Under preferable conditions, this reaction is usually completed in 0.5 to 12 hours.
  • the compound of formula (IV) is reacted with a nitrite in the presence of copper halide, in the presence or absence of methylene halide, the copper halide is monovalent or divalent, and the compound of formula (IV ) Is used in an amount of 0.5 to 10 equivalents.
  • the methylene halide is used in an amount of 1 to 10 equivalents based on the compound of the formula (IV), if necessary.
  • the halogenated methylene used is preferably dibromomethane or diiodomethane.
  • the nitrite is used in an amount of 1 to 5 equivalents relative to the compound of formula (IV).
  • the halogenation reaction is bromination in an organic solvent such as tetrahydrofuran, dioxane or acetonitrile, the halogenation is carried out in the presence of 2 to 10 equivalents of copper dibromide with respect to the compound of formula (IV).
  • reaction temperature is 0 to 150 ° C, preferably 50 to 100 ° C. Under preferable conditions, this reaction is completed in 0.5 to 12 hours.
  • the ring-forming reaction in the present invention (Step 3 in the above reaction scheme) is usually performed by using a carboxylic acid hydrazide compound (V), cyanamide (NH 2 CN), aminoguanidine bicarbonate, S-ethylisothiourea hydrobromide, or the like.
  • the reaction is carried out by reacting the guanidine agent in the presence of an acid and then in the presence of a base.
  • cyanamide is preferably used.
  • the amount of the guanidine agent used is 1 to 20 equivalents, preferably 2 to 10 equivalents, relative to the compound of formula (V).
  • organic acids such as p-toluenesulfonic acid and methanesulfonic acid, and inorganic acids such as hydrochloric acid and sulfuric acid are used.
  • p-toluenesulfonic acid is used.
  • the amount of the acid used is 0.5 to 3 equivalents, preferably 1 to 2 equivalents, relative to the compound of formula (V).
  • an organic base such as triethylamine or diisopropylethylamine, or an inorganic base such as potassium carbonate is used, but triethylamine is preferably used.
  • the base is used in an amount of 2 to 20 equivalents, preferably 5 to 15 equivalents, relative to the compound of formula (V).
  • reaction solvent ethanol, isopropyl alcohol, acetonitrile or water, or a mixed solvent thereof is used, and ethanol is preferably used.
  • the reaction temperature is 30 to 120 ° C., preferably 50 to 100 ° C. Under preferred conditions, the reaction is completed in 1 to 24 hours for the acid treatment step and 5 to 120 hours for the base treatment step.
  • Compounds (II), (III), (IV) and (V) used in the production method of the present invention are novel compounds.
  • Compound (III) can be produced by the method described in 1) to 3) of Example 4 described later.
  • the compound (V) in which L as a leaving group is a chlorine atom can be produced by the method described in 1) to 3) of Example 1 described later.
  • Compound (V) in which L as a leaving group is another halogen atom is obtained by replacing 1-chloro-3-iodopropane used in 2) of Example 1 with the corresponding 1-halo-3-iodopropane.
  • it can be produced by performing the same reaction in place of 1,3-dibromopropane.
  • the compound of the formula (I) produced in the present invention and the intermediate used in the production thereof may be a salt.
  • the compound of the formula (I) or a free salt of the intermediate is a conventional salt. It can be made into a salt by adding a forming step.
  • Specific examples of the salt include inorganic acid salts such as sulfate, nitrate, phosphate, hydrochloride or hydrobromide, acetate, maleate, tartrate, fumarate or citrate.
  • organic carboxylates or organic sulfonates such as methanesulfonate, toluenesulfonate, and camphorsulfonate.
  • the resulting suspension was further cooled to ice cooling, filtered, washed with heptane (150 mL), and dried under reduced pressure to obtain 27.7 g (content 93%) of the first crystal of the title compound. 1.43 g (content 87%) of the second crystal was obtained from the filtrate. Together, the title compound was obtained as white crystals in a yield of 84%.
  • Hydrazine monohydrate (6.84 mL, 141 mmol) was added under ice cooling, and after stirring for 2 hours, hydrazine monohydrate (4.56 mL, 94 mmol) was further added under ice cooling. After stirring for 30 minutes, the mixture was diluted with 5% NaCl aqueous solution (200 mL) and separated. The organic layer was washed with water (200 mL) and concentrated under reduced pressure at 40 ° C. or lower. When a mixed solution (100 mL) of MTBE and heptane 1: 3 was added to the residue and stirred at room temperature, a solid precipitated. To this was further added heptane (50 mL), and the mixture was cooled with ice and filtered.
  • the crystals were washed with a cooled mixture of MTBE and heptane 1: 3 (100 mL). Further, it was washed with a mixed solution (100 mL) of MTBE and heptane 1: 1 and dried under reduced pressure to obtain 6.4 g (content 100%, 100% ee) of the title compound in a yield of 41.3%.
  • the present invention is useful as an A ⁇ production inhibitor (8S) -2- ⁇ (E) -2- [6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridin-2-yl ] Vinyl ⁇ -8- [2- (trifluoromethyl) phenyl] -5,6,7,8- [1,2,4] triazolo [1,5-a] pyridine or a salt thereof . Also provided are novel synthetic intermediates useful for this preparation.

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

Abstract

La présente invention concerne un procédé par lequel la (8S)-2-{(E)-2-[6-méthoxy-5-(4-méthyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-[2-(trifluorométhyl)phényl]-5,6,7,8-tétrahydro[1,2,4]triazolo[1,5-a]pyridine représentée par la formule (I) ou un de ses sels, utile dans le traitement de maladies neurodégénératives telles que la maladie d'Alzheimer et le syndrome de Down, peut être produite d'une manière suffisamment avantageuse du point de vue commercial. Ledit procédé comprend l'étape consistant à soumettre un composé représenté par la formule (II) (dans laquelle X représente un atome d'halogène) ou un de ses sels, et un composé représenté par la formule (III) ou un de ses sels, à une réaction de couplage.
PCT/JP2010/052808 2009-02-26 2010-02-24 Procédé de production de composés polycycliques et de leurs intermédiaires WO2010098332A1 (fr)

Applications Claiming Priority (2)

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JP2009-043266 2009-02-26
JP2009043266A JP2012121809A (ja) 2009-02-26 2009-02-26 多環式化合物の製造法およびその中間体

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8697673B2 (en) 2011-03-31 2014-04-15 Pfizer Inc. Bicyclic pyridinones
US8916564B2 (en) 2012-09-21 2014-12-23 Pfizer Inc. Substituted pyrido[1,2-a]pyrazines for the treatment of neurodegenerative and neurological disorders
US9765073B2 (en) 2015-02-03 2017-09-19 Pfizer Inc. Cyclopropabenzofuranyl pyridopyrazinediones
CN107434780A (zh) * 2016-05-26 2017-12-05 上海韬勤生物医药科技有限公司 一种ar-13324的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007102580A1 (fr) * 2006-03-09 2007-09-13 Eisai R & D Management Co., Ltd. Dérivé polycyclique de cinnamide
JP2008542376A (ja) * 2005-06-01 2008-11-27 ワイス クラスＤのβラクタマーゼ阻害剤としての三環系６−アルキリデンペネム類
WO2009028588A1 (fr) * 2007-08-31 2009-03-05 Eisai R & D Management Co., Ltd. Composé polycyclique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008542376A (ja) * 2005-06-01 2008-11-27 ワイス クラスＤのβラクタマーゼ阻害剤としての三環系６−アルキリデンペネム類
WO2007102580A1 (fr) * 2006-03-09 2007-09-13 Eisai R & D Management Co., Ltd. Dérivé polycyclique de cinnamide
WO2009028588A1 (fr) * 2007-08-31 2009-03-05 Eisai R & D Management Co., Ltd. Composé polycyclique

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8697673B2 (en) 2011-03-31 2014-04-15 Pfizer Inc. Bicyclic pyridinones
US9067934B2 (en) 2011-03-31 2015-06-30 Pfizer Inc. Bicyclic pyridinones
US8916564B2 (en) 2012-09-21 2014-12-23 Pfizer Inc. Substituted pyrido[1,2-a]pyrazines for the treatment of neurodegenerative and neurological disorders
US9193726B2 (en) 2012-09-21 2015-11-24 Pfizer Inc. Substituted pyrido[1,2-a]pyrazines for the treatment of neurodegenerative and neurological disorders
US9751877B2 (en) 2012-09-21 2017-09-05 Pfizer Inc. Substituted pyrido[1,2-a]pyrazines for the treatment of neurodegenerative and neurological disorders
US9765073B2 (en) 2015-02-03 2017-09-19 Pfizer Inc. Cyclopropabenzofuranyl pyridopyrazinediones
CN107434780A (zh) * 2016-05-26 2017-12-05 上海韬勤生物医药科技有限公司 一种ar-13324的制备方法
CN107434780B (zh) * 2016-05-26 2020-08-07 上海韬勤生物医药科技有限公司 一种ar-13324的制备方法

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