WO2010098496A1 - Process for producing tetrahydrotriazolopyridine derivative - Google Patents

Process for producing tetrahydrotriazolopyridine derivative Download PDF

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WO2010098496A1
WO2010098496A1 PCT/JP2010/053379 JP2010053379W WO2010098496A1 WO 2010098496 A1 WO2010098496 A1 WO 2010098496A1 JP 2010053379 W JP2010053379 W JP 2010053379W WO 2010098496 A1 WO2010098496 A1 WO 2010098496A1
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formula
group
salt
compound
represented
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French (fr)
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Toshiyuki Uemura
Takeo Sasaki
Yorihisa Hoshino
Minetaka Isomura
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Eisai R&D Management Co., Ltd.
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/20—Preparation of carboxylic acid nitriles by dehydration of carboxylic acid amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/30—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same unsaturated acyclic carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/40—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/06—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid amides

Definitions

  • the present invention relates to a process for producing a tetrahydrotriazolopyridine derivative. More particularly, the present invention relates to a process for producing a 2-vinyl-5,6,7,8-tetrahydro[l,2,4]triazolo[l,5-a]pyridine derivative represented by the formula (I): [Formula 1]
  • a and B each represent an aryl group or a heteroaryl group which may have a substituent, and to a production intermediate thereof.
  • Such a compound in particular, (8S)-2- ⁇ (E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl ⁇ -8-[2-
  • Alzheimer's disease is a disease characterized by degeneration and loss of neurons as well as formation of senile plaques and neurofibrillary degeneration.
  • a symptom improving agent typified by an acetylcholinesterase inhibitor
  • a fundamental remedy to inhibit progression of the disease has not yet been developed. It is necessary to develop a method for controlling the cause of the onset of pathology in order to create a fundamental remedy for Alzheimer's disease.
  • a ⁇ -proteins such as amyloid- ⁇ 40 and amyloid- ⁇ 42 (hereinafter referred to as A ⁇ 40 and A ⁇ 42), which are metabolites of amyloid precursor proteins (hereinafter referred to as APP), are highly involved in degeneration and loss of neurons and onset of symptoms of dementia (see NON-PATENT DOCUMENTS 1 and 2, for example). Accordingly, a compound that reduces the production of A ⁇ 40 and A ⁇ 42 is expected as a progression inhibitor or prophylactic agent for Alzheimer's disease. [0003]
  • PATENT DOCUMENT 1 discloses the fact that a compound represented by the following formula: [Formula 2]
  • U represents a nitrogen atom or the like
  • V represents an oxygen atom or the like
  • G represents an oxygen atom or the like
  • R 1 represents a hydrogen atom, a halogen atom or the like
  • R 2 represents a hydrogen atom, an alkyl group or the like
  • 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
  • R 10 represents an alkyl group or the like
  • is a ⁇ -secretase modulator involved in the inhibition of production of A ⁇ 40 and A ⁇ 42 and also discloses a process for producing such a compound.
  • PATENT DOCUMENT 2 discloses the fact that a 2-[4-(imidazolyl)phenyl]vinyl- heterocycle derivative represented by the following formula: [Formula 3]
  • PATENT DOCUMENT 3 discloses the fact that a compound represented by the following formula: [Formula 4]
  • a ⁇ represents an imidazolyl group or the like which may be substituted with a Cl -6 alkyl group
  • Ar 2 represents a phenyl group or the like which may be substituted with a C 1-6 alkoxy group
  • X 1 represents a double bond or the like
  • Het represents an imidazolyl group or the like which may be substituted with a Cl -6 alkyl group or the like, inhibits the production of amyloid- ⁇ 40 and 42 from amyloid precursor proteins, and also discloses a process for producing such a compound.
  • PATENT DOCUMENT 1 WO 2008/137139
  • PATENT DOCUMENT 2 WO 2008/097538
  • PATENT DOCUMENT 3 WO 2007/102580
  • NON-PATENT DOCUMENT 1 Klein WL, et al., Alzheimer's disease-affected brain: Presence of oligomeric A ⁇ ligands (ADDLs) suggests a molecular basis for reversible memory loss,
  • NON-PATENT DOCUMENT 2 Nitsch RM, et al., Antibodies against ⁇ -amyloid slow cognitive decline in Alzheimer's disease, Neuron, 2003, May 22; 38, p. 547-554.
  • a 2-[5-(imidazolyl)pyridin-2-yl]vinyl derivative represented by the formula (I), typically the formula (1-3), is a novel compound that has not yet been described in any documents. Therefore, a process for producing the same has not yet been known, and there is a need to develop an efficient process for producing the same.
  • an object of the present invention is to provide a process for producing a 2-vinyl-5,6,7,8-tetrahydro[l,2,4]triazolo[l,5-a]pyridine derivative, in particular, (8S)-2- ⁇ (E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl ⁇ -8-[2- (trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[l,2,4]triazolo[l,5-a]pyridine or a salt thereof, which has an amyloid- ⁇ production reducing effect, and to provide a production intermediate thereof and a process for producing the same.
  • the present invention relates to:
  • a and B are as defined above, or a salt thereof in a solvent in the presence of an acid
  • Substituent Group A a halogen atom, a lower alkyl group having 1 to 6 carbon atoms which may have 1 to 3 substituents selected from Substituent Group Al, a lower alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 substituents selected from Substituent Group Al, an aryl group which may have 1 to 3 substituents selected from Substituent Group A2 and a heteroaryl group which may have 1 to 3 substituents selected from Substituent Group A2;
  • Substituent Group Al a hydroxyl group, a halogen atom, a cyano group and a lower alkoxy group having 1 to 6 carbon atoms;
  • Substituent Group A2 a halogen atom and a lower alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms;
  • Substituent Group B a halogen atom, a cyano group, a nitro group, a lower alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms and a lower alkoxy group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms;
  • a 1 represents an aryl group which may have 1 to 3 substituents selected from Substituent Group Al or a heteroaryl group which may have 1 to 3 substituents selected from Substituent Group Al
  • a 2 represents an aryl group which may have 1 to 3 substituents selected from Substituent Group A2 or a heteroaryl group which may have 1 to 3 substituents selected from Substituent Group A2
  • B is as defined in [1] above, or a salt thereof using a compound represented by the formula (II- 1): [Formula 8]
  • a 1 , A 2 and B are as defined above, or a salt thereof;
  • Substituent Group Al a hydroxyl group, a halogen atom, a cyano group and a lower alkoxy group having 1 to 6 carbon atoms;
  • Substituent Group A2 a halogen atom and a lower alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms;
  • a 1 is a phenyl group which may have 1 to 3 substituents selected from Substituent Group Al or a pyridyl group which may have 1 to 3 substituents selected from Substituent Group Al;
  • a 2 is an imidazolyl group which may have 1 to 3 substituents selected from Substituent Group A2;
  • the present invention can particularly produce a compound represented by the formula (1-3): [Formula 26]
  • the present invention also provides a production intermediate for producing the compound of the formula (1-3) in a high yield and a process for producing the same.
  • EMBODIMENT FOR CARRYING OUT THE INVENTION [0011]
  • a structural formula of a compound may represent a certain isomer for convenience.
  • the present invention includes all isomers and isomer mixtures such as geometric isomers which can be generated from the structure of a compound, optical isomers based on asymmetric carbon, stereoisomers and tautomers.
  • the present invention is not limited to the description of a chemical formula for convenience and may include any one of the isomers or mixtures thereof.
  • the compound of the present invention may have an asymmetric carbon atom in the molecule and exist as an optically active compound or racemate, and the present invention includes each of the optically active compound and the racemate without limitations.
  • crystal polymorphs of the compound may be present, the compound is not limited thereto as well and may be present as a single crystal form or a mixture of single crystal forms.
  • the compound may be an anhydride or a solvate such as a hydrate.
  • any compound used in the production process of the present invention or any target compound produced by the process may be a salt.
  • the salt include inorganic acid salts (such as sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, hydrofluorides, hydrochlorides, hydrobromides and hydroiodides), organic carboxylates (such as acetates, oxalates, maleates, tartrates, fumarates and citrates), organic sulfonates (such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates and camphorsulfonates), amino acid salts (such as aspartates and glutamates), quaternary amine salts, alkali metal salts (such as sodium salts and potassium salts) and alkali earth metal salts (such as magnesium salts and calcium salts).
  • the "aryl group” refers to a monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring group having 6 to 14 carbon atoms, for example.
  • the group include 6- to 14-membered monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring groups such as a phenyl group, an indenyl group, a naphthyl group, an azulenyl group, a heptalenyl group, a biphenyl group, a fluorenyl group, a phenalenyl group, a phenanthrenyl group and an anthracenyl group.
  • a phenyl group is preferable, for example.
  • heteroaryl group refers to a monocyclic, bicyclic or tricyclic aromatic heterocyclic group having 5 to 14 carbon atoms.
  • the group include (1) nitrogen-containing aromatic heterocyclic groups such as a pyrrolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a pyrazolinyl group, an imidazolyl group, an indolyl group, an isoindolyl group, an indolizinyl group, a purinyl group, an indazolyl group, a quinolyl group, an isoquinolyl group, a quinolizinyl group, a phthalazinyl group, a naphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group,
  • halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like and is preferably a fluorine atom, a chlorine atom or a bromine atom.
  • lower alkyl group having 1 to 6 carbon atoms include linear or branched alkyl groups such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a tert-butyl group, an n-pentyl group, an i-pentyl group, a neopentyl group, an n-hexyl group, a 1-methylpropyl group, an 1,2- dimethylpropyl group, a 1-ethylpropyl group, a l-methyl-2-ethylpropyl group, a l-ethyl-2- methylpropyl group, a 1,1,2-trimethylpropyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl
  • the "lower alkoxy group having 1 to 6 carbon atoms” refers to an alkyl group having 1 to 6 carbon atoms in which a hydrogen atom is replaced by an oxygen atom.
  • the group include a methoxy group, an ethoxy group, an n-propoxy group, an i- propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentoxy group, an i-pentoxy group, a sec-pentoxy group, a tert-pentoxy group, an n-hexoxy group, an i-hexoxy group, a 1,2-dimethylpropoxy group, a 2-ethylpropoxy group, a l-methyl-2- ethylpropoxy group, a l-ethyl-2-methylpropoxy group, a 1,1,2-trimethylpropoxy group, a 1,1,2- trimethylpropoxy group, a 1,1,
  • the "lower alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms” refers to a lower alkyl group in which a hydrogen atom in the aforementioned lower alkyl group may be replaced by a halogen atom.
  • the group include a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trichloromethyl group, a 1,2-difluoroethyl group, a 2,2-difluoroethyl group, a 1,2-dichloroethyl group, a 1,2-difluoropropyl group and a 2,2-difluoropropyl group.
  • lower alkoxy group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms refers to a lower alkoxy group in which a hydrogen atom in the aforementioned lower alkoxy group may be replaced by a halogen atom.
  • the group include a monofluoromethyloxy group, a difluoromethyloxy group, a trifluoromethyloxy group and a trichloromethyloxy group.
  • Substituent Group A a halogen atom, a lower alkyl group having 1 to 6 carbon atoms which may have 1 to 3 substituents selected from Substituent Group Al, a lower alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 substituents selected from Substituent Group Al, an aryl group which may have 1 to 3 substituents selected from Substituent Group A2 and a heteroaryl group which may have 1 to 3 substituents selected from Substituent Group A2;
  • Substituent Group Al a hydroxyl group, a halogen atom, a cyano group and a lower alkoxy group having 1 to 6 carbon atoms;
  • Substituent Group A2 a halogen atom and a lower alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms
  • Substituent Group B a halogen atom, a cyano group, a nitro group, a lower alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms and a lower alkoxy group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms.
  • Step 1 is a process for producing a compound (I) from a compound (II) as a raw material.
  • Step l Step 1 is a step of heating an N'-(4-cyanobutyl)acrylohydrazide derivative represented by the formula (II) in a solvent in the presence of an acid to cause intramolecular cyclization reaction to convert the compound (II) to a 2-vinyl-5,6,7,8- tetrahydro[l,2,4]triazolo[l,5-a]pyridine derivative represented by the formula (I) (hereinafter Step 1). [0027]
  • the compound of the formula (II) can be produced from a commercially available product by a method known to a person skilled in the art according to a production process described later in Production Processes 2, 4, 5 and 6 or Examples.
  • a compound (II-3) of the formula (II), wherein A is a 6-methoxy-5-(4-methyl-lH-imidazol-l- yl)pyridine-2-yl group and B is a 2-(trifluoromethyl)phenyl group can be produced by producing a compound (9) from a compound (6) as shown in the later-described Production Process 5; further producing a compound (1) from the compound (9) as shown in Production Process 4; separately producing a compound (2) from a compound (13) as shown in Production Process 6; and then reacting the compound (1) with the compound (2) as shown in Production Process 2.
  • the compound of the formula (II), wherein A and B are other functional groups, can be produced by producing a compound corresponding to the compound (1) by the same method as shown in Production Processes 5 and 4 using a compound in which the 2-(trifluoromethyl)phenyl group in the compound (6) of Preparation Process 5 is replaced by the other functional group B; separately producing a compound corresponding to the compound (2) by the same method as shown in Production Process 6 using a compound in which the 6-methoxy-5-(4-methyl-lH- imidazol-l-yl)pyridin-2-yl group in the compound (13) of Preparation Process 6 is replaced by the other functional group A; and reacting this compound with the compound corresponding to the compound (1) in the same manner as in Step 2-1 of Production Process 2. [0028]
  • the reaction in Step 1 is performed out using an acid such as acetic acid.
  • the solvent used in this reaction is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent. Tetrahydrofuran, benzene, toluene or N,N-dimethylformamide may be used, for example.
  • the reaction temperature is not particularly limited and is usually room temperature to 100 0 C. [0029]
  • Step 1 it is preferable to produce a compound represented by the formula (1-1) where A is the formula A 2 -Ai-: [Formula 29]
  • a 1 , A 2 and B are as defined above.
  • Production Process 2 is a process for producing a compound (1-3) from a compound (2) as a raw material.
  • a compound (II-3) is a novel compound that has not yet been described in any documents. [0032] Step 2-1
  • Step 2-1 is a step of obtaining a compound (II-3) by reductive animation reaction of a compound (1) with a compound (2).
  • This reaction can be performed under the same conditions as those usually used in reductive animation reaction of a carbonyl compound with an amine compound.
  • the reduction reaction used in this reaction is not particularly limited.
  • Examples of the reduction reaction include reductive animation reaction using a reducing agent such as borane, a boron hydride complex compound or formic acid; and catalytic reduction reaction using a metal catalyst in a hydrogen atmosphere.
  • Examples of the reductive animation reaction using a boron hydride complex compound include reactions according to documents such as W.S. Emerson, Organic Reactions, 4, 174 (1948); CF. Lane, Synthesis, 135 (1975); J.C. Stowell and SJ. Pedegimas, Synthesis, 127 (1974); and A.F. Abdel-Magid, K.G. Carson, B.D. Harris, CA. Maryanoff, and R.D. Shah, Journal of Organic Chemistry, 61, 3849 (1996).
  • the compound (2) used may be a free form or a salt.
  • a hydrochloride, a hydrobromide or the like of the compound (2) can be preferably used.
  • the boron hydride complex compound examples include sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride.
  • the solvent is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent.
  • Specific examples of the solvent that can be used include methanol, ethanol, tetrahydrofuran, dichloromethane and 1,2-dichloroethane. More preferable results such as an improved yield can be achieved by performing this reaction in the presence of an acid.
  • an acid is not particularly limited.
  • the acid include mineral acids such as hydrochloric acid, organic acids such as acetic acid, and Lewis acids such as zinc chloride, a boron trifluoride-diethyl ether complex and titanium (IV) tetraisopropoxide.
  • the reaction temperature is not particularly limited and is usually -78°C to solvent reflux temperature, and preferably ice-cold temperature to room temperature.
  • the solvent is not particularly limited insofar as it does not inhibit the reaction. An excess of formic acid may be used as a solvent.
  • the reaction temperature is not particularly limited and is usually 50 0 C to solvent reflux temperature.
  • Heating to a high temperature of 150 to 250 0 C by use of a sealed pressure vessel may provide excellent results such as a reduced reaction time.
  • the solvent used in the catalytic reduction reaction in a hydrogen atmosphere is not particularly limited insofar as it does not inhibit the reaction.
  • the solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane and ethyl acetate.
  • the metal catalyst used in the reaction include palladium-carbon, palladium hydroxide-carbon, platinum oxide and Raney nickel.
  • the reaction conditions are not particularly limited, and the reaction can be performed at room temperature to solvent reflux temperature and at normal pressure to 150 atm, and preferably at room temperature to 60 0 C and at normal pressure to 5 atm. More preferable results such as an improved yield can be achieved by performing this reaction in the presence of an acid.
  • Such an acid is not particularly limited.
  • Preferable examples of the acid include mineral acids such as hydrochloric acid and organic acids such as acetic acid.
  • Step 2-2 is a step of heating the compound (II-3) in a solvent to cause intramolecular cyclization reaction to convert the compound (II-3) to a compound (1-3).
  • the reaction may be performed under acidic, neutral or basic conditions and is preferably performed using an acid such as acetic acid.
  • the solvent used in the reaction is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent. Tetrahydrofuran, benzene, toluene or N 5 N- dimethylformamide may be used, for example.
  • the reaction temperature is not particularly limited and is usually 50 0 C to 100 0 C. [0034]
  • Production Process 3 is a process alternative to the aforementioned Production Process 2 to produce a compound (1-3) and is a process for producing a compound (1-3) by reacting a compound (10) with a compound (11). [0036] Step 3
  • Step 3 is a step of obtaining a compound (1-3) by condensation cyclization of a compound (10) (2-imino-3-[2-(trifluoromethyl)phenyl]piperidin-l-amine) with a compound (11) ((2E)-3-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]acrylic acid).
  • a method of activating a carboxylic acid moiety is effective for this reaction.
  • Examples of the method include an acid chloride method, a method using a carbodiimide condensing agent and a method using a phosphoryl azide condensing agent.
  • the solvent used in the reaction is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent. Tetrahydrofuran, benzene, toluene or N,N-dimethylformamide may be used, for example.
  • the reaction temperature is not particularly limited and is usually 50 0 C to 100 0 C.
  • the compound (10) can be produced from a commercially available product by a method known to a person skilled in the art according to a production process described later in Production Process 4 or Examples.
  • the compound (11) can be produced from a commercially available product by a method known to a person skilled in the art according to a production process described later in Production Process 6.
  • the compound (10) used may be a free form or a salt.
  • a hydrochloride, a hydrobromide or the like of the compound (10) can be preferably used.
  • Production Process 4 is a process for producing a compound (1) and a compound (10) from a compound (9) as a raw material.
  • the compound (1) and the compound (9) are novel compounds that have not yet been described in any documents. [0039] Step 4-1
  • Step 4-1 is a step of obtaining a compound (1) from a compound (9) by oxidation reaction.
  • This reaction is a reaction of converting a methyl halide to an aldehyde by oxidation reaction.
  • the oxidizing agent used in the reaction include DMSO (Kornblum oxidation), nitro compounds (Haas reaction), hexamine (Sommelet reaction), p- nitrosodimethylaniline (Krohnke reaction) and amine oxides.
  • DMSO Korean oxidation
  • nitro compounds Haas reaction
  • hexamine Schommer reaction
  • p- nitrosodimethylaniline Krohnke reaction
  • amine oxides amine oxides.
  • DMSO Korean oxidation
  • Step 4-2 is a step of converting a nitrile compound (9) to an imidate compound
  • the imidate compound obtained in this reaction can be synthesized by the Pinner method in which an alcohol is added to a nitrile in the presence of hydrogen chloride or by a method of adding an alcohol to a nitrile in the presence of a base (see P. Raynaud, R.C. Moreau, Bull. Soc. Chem. Fr., 1964, 2997 or A. W. Dox, Org. Synth., I, 5 (1941), for example).
  • Step 4-3 is a step of obtaining a compound (10) from the compound (12).
  • the imidate compound (12) can be converted to a compound (10) by reaction with hydrazine and intramolecular cyclization.
  • the compound (9) can be produced from a commercially available product by a method known to a person skilled in the art according to a production process described later in Production Process 5 or Examples.
  • Production Process 5 is a process for producing a compound (9) from a compound
  • Step 5-1 is a step of obtaining a compound (7) from a compound (6) by oxidative hydrolysis.
  • This reaction is not particularly limited insofar as the conditions are similar to those in this reaction.
  • a known method described in many documents such as described in Evans, D.A.; Bartroli, J.; Shih, T.I., J. Am. Chem. Soc, 1981, 103, 2127-2129) may be used.
  • an acyloxazolidinone compound is reacted with hydrogen peroxide and an alkali hydroxide such as lithium hydroxide in a water-miscible solvent such as tetrahydrofuran in the presence of water to convert the compound to carboxylic acid.
  • the reaction temperature is preferably O 0 C to room temperature.
  • Step 5-2 is a step of converting the carboxylic acid (7) to an amide (8).
  • This reaction of converting carboxylic acid to amide is not particularly limited insofar as the conditions are similar to those in this reaction.
  • a known method described in many documents such as described in Jikken Kagaku Koza (Courses in Experimental Chemistry), 4th edition, 22, Maruzen Co., Ltd., 1992, p. 138-144) may be used.
  • Step 5-3 is a step of converting the amide compound (8) to a nitrile compound (9) by dehydration.
  • This reaction is not particularly limited insofar as the conditions are similar to those in this reaction.
  • a known method described in many documents such as described in Jikken Kagaku Koza (Courses in Experimental Chemistry), 4th edition, 20, Maruzen Co., Ltd., 1992, p. 449-450 may be used.
  • Examples of the dehydrating agent used in this reaction include phosphorus pentoxide, phosphorus pentachloride, thionyl chloride, toluenesulfonyl chloride, methanesulfonyl chloride, chlorosulfonyl cyanate, N,N-dicyclohexylcarbodiimide and 2- chlorobenzoxazolium salts.
  • This reaction is performed by a method using a solvent or by a method of distilling a reaction mixture by directly heating without a solvent.
  • the solvent used in the method using a solvent is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent.
  • the solvent include acetonitrile, tetrahydrofuran, 1,4- dioxane, 1 ,2-dimethoxyethane, benzene, toluene, xylene, l-methyl-2-pyrrolidone and N,N- dimethylformamide.
  • the compound (6) can be produced from a commercially available product by a method known to a person skilled in the art according to a production process described later in Examples. [0047]
  • Step 6-2 Step 6-1
  • Production Process 6 is a process for producing a compound (2) or a compound
  • Step 4-1 is a step of obtaining a compound (16) or a compound (17) by Mizoroki- Heck reaction of a compound (13) with a compound (14) or a compound (15).
  • a halogen compound or triflate compound (13), wherein X represents a chlorine atom, a bromine atom, an iodine atom or a sulfonate group such as a trifluoromethanesulfonate group is preferably coupled with 1.0 to 5.0 equivalents of an alkene compound (14) or (15) with respect to the compound (13) in the presence of 0.01 to 0.2 equivalent of a transition metal catalyst with respect to the compound (13), for example.
  • This reaction is preferably performed in the presence of a solvent from the viewpoint of handleability and stirring efficiency.
  • the solvent used varies according to the starting material and the transition metal catalyst used, and is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent.
  • the solvent include acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, l-methyl-2-pyrrolidone and N,N-dimethylformamide.
  • the reaction temperature must be a temperature that can complete the coupling reaction, and is preferably room temperature to 150°C. This reaction is performed preferably in an inert gas atmosphere, and more preferably in a nitrogen or argon atmosphere.
  • the transition metal catalyst is preferably a palladium complex, for example, and more preferably a known palladium complex such as palladium (II) acetate, dichlorobis(triphenylphosphine)palladium (II), tetrakis(triphenylphosphine)palladium (0) or tris(dibenzylideneacetone)dipalladium (0). It is also preferable to appropriately add a phosphorus ligand (preferably triphenylphosphine, tri-o- tolylphosphine, tri-tert-butylphosphine or 2-(di-tert-butylphosphino)biphenyl, for example) in order to make the reaction efficiently proceed.
  • a phosphorus ligand preferably triphenylphosphine, tri-o- tolylphosphine, tri-tert-butylphosphine or 2-(di-tert-butylphosphino)bi
  • a preferable result may be achieved in the presence of a base.
  • the base used is not particularly limited insofar as it is used in a coupling reaction similar to this reaction.
  • Preferable examples of the base include triethylamine, N 5 N- diisopropylethylamine, N,N-dicyclohexylmethylamine and tetrabutylammonium chloride.
  • Step 6-2 is a step of obtaining a compound (2) from the compound (16) by deprotection reaction.
  • This deprotection reaction varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction.
  • a known method described in many documents may be used for the reaction (see T. W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., 1999, p. 615-626).
  • a compound having a tert-butyl carbamate group as a protecting group is stirred in a solvent in the presence of 1.0 to 100.0 equivalents of an acid with respect to the compound, for example.
  • the acid used include inorganic acids such as hydrochloric acid and sulfuric acid; and organic acids such as trifluoroacetic acid and methanesulfonic acid.
  • the solvent used is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent.
  • the solvent include ethyl acetate, methanol, ethanol, 1,4-dioxane, methylene chloride, chloroform, methanol, isopropyl alcohol, N,N-dimethylformamide and N-methylpyrrolidone.
  • the reaction temperature must be a temperature that can complete the reaction without promoting formation of an undesirable byproduct, and is preferably 0 to 100 0 C, for example.
  • Step 6-3 Step 6-3 is a step of obtaining a compound (11) from the ester compound (17) by hydrolysis reaction. [0053]
  • the carboxylic acid compound (11) is prepared by hydrolysis of the ester compound (17).
  • Step 6-3 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction.
  • a known method described in many documents may be used for the reaction (see Shin Jikken Kagaku Koza (New Courses in Experimental Chemistry), vol.22, Yuki Gosei (Organic Synthesis) [IV], edited by The Chemical Society of Japan, Maruzen Co., Ltd., November 1992, p.6-11, for example).
  • an ester compound (8) is stirred in a solvent in the presence of 1.0 to 100.0 equivalents of a base or acid with respect to the ester compound (8), for example.
  • the base used varies according to the starting material and is not particularly limited.
  • Preferable examples of the base include sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate and barium carbonate.
  • the acid used varies according to the starting material and is not particularly limited.
  • Preferable examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid; organic acids such as trifluoroacetic acid and p-toluenesulfonic acid; and Lewis acids such as boron trichloride.
  • the solvent used varies according to the starting material, and is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent.
  • Preferable examples of the solvent include alcohol solvents such as methanol, ethanol and ethylene glycol; ether solvents such as tetrahydrofuran; water; and mixed solvents thereof.
  • reaction temperature must be a temperature that can complete the reaction without promoting formation of an undesirable by-product, and is preferably room temperature to 100 0 C, for example.
  • DMPU 1 ,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone
  • Pd2DB A3 Tris(dibenzylideneacetone)dipalladium
  • Pd(t-Bu3P)2 Bis(tri-t-butyl ⁇ hos ⁇ hine)palladium [0056]
  • Patterns are designated as s: singlet, d: doublet, t: triplet, q: quartet, br: broad.
  • Triethylamine (51.5 mL, 368 mmol) was added to a suspension of 2- trifluoromethylphenylacetic acid (37.6 g, 184 mmol) and (s)-(+)-4-phenyl-2-oxazolidinone (15 g, 92 mmol) in toluene (450 mL) at room temperature.
  • Pivaloyl chloride (22.7 mL, 184 mmol) was added dropwise to the suspension with stirring at room temperature. The resulting suspension was heated under reflux with stirring for 18 hours. After cooling to room temperature, 2 N hydrochloric acid (150 mL) was added, followed by extraction.
  • the organic layer was sequentially washed with a saturated sodium bicarbonate solution (150 mL) twice, a 5% sodium chloride solution (150 mL) and water (150 mL) and concentrated under reduced pressure.
  • Ethyl acetate (45 mL) was added to the resulting solid, and the solid was completely dissolved by heating to 5O 0 C.
  • Heptane (180 mL) was added to the solution, followed by gradually cooling to room temperature.
  • the resulting suspension was further cooled to ice-cold temperature, and then filtered, washed with heptane (150 mL) and dried under reduced pressure to obtain 27.7 g (content: 93%) of first crystals of the title compound. From the filtrate, 1.43 g (content: 87%) of second crystals were obtained.
  • the crystals were combined to obtain the title compound as white crystals in a yield of 84%.
  • Example 2 The compound obtained in Example 2 (4000 mg, 9.09 mmol) was weighed in a reaction vessel. Subsequently, the atmosphere in the reaction vessel was replaced by nitrogen gas. Tetrahydrofuran (40 ml) and water (20 ml) were added to the reaction vessel. After dissolution at room temperature, a 30% hydrogen peroxide solution (1.24 mL, 1.2 eq) was added dropwise at 0 0 C. Lithium hydroxide monohydrate (458 mg, 10.91 mmol) was further added, followed by stirring at that temperature for 45 minutes. A 10% sodium thiosulfate pentahydrate solution (48 mL) was added to the reaction solution, followed by stirring.
  • Example 3 The compound obtained in Example 3 (2.596 g, purity: 87.4 wt%, 8.08 mmol) was weighed in a reaction vessel. Subsequently, the atmosphere in the reaction vessel was replaced by nitrogen gas. DMF (46 mL) was added to the reaction vessel, followed by dissolution at room temperature. Then, ammonium chloride (2161 mg, 40.4 mmol, 5 eq), diisopropylethylamide (13 mL, 74.6 mmol, 9.2 eq), HOBt (1324 mg, 9.80 mmol) were added, respectively. PyBOP (5097 mg, 9.80 mmol) was further added, followed by stirring at room temperature for 10.5 hours.
  • Example 4 The compound obtained in Example 4 (2059 mg, 7.36 mmol) was weighed in a reaction vessel. Subsequently, the atmosphere in the reaction vessel was replaced by nitrogen gas. DMF (16 mL) was added to the reaction vessel, followed by dissolution at room temperature. Then, toluene (33 mL) was added. After cooling to -35°C, thionyl chloride (1073 ⁇ L, 14.72 mmol, 2 eq) was added dropwise, followed by stirring for 1.5 hours.
  • Example 6 The compound obtained in Example 6 (1892 mg, 7.23 mmol) was weighed in a reaction vessel. Subsequently, the atmosphere in the reaction vessel was replaced by nitrogen gas. DMSO (20 mL) was added to the reaction vessel, followed by dissolution at room temperature. Then, 2,4,6-collidine (1528 ⁇ L, 11.6 mmol) and sodium iodide (3492 mg, 23.3 mmol) were added. The mixture was heated at 80 0 C for 15 hours and cooled to room temperature. Water and ethyl acetate were introduced into the reaction mixture, and then the organic layer was separated. The aqueous layer was extracted with ethyl acetate.
  • Tri(o-tolyl)phosphine (885mg, 2.90mmol), Palladium (II) acetate (327mg, 1.45mmol) and N,N-diisopropylethylamine (12.7mL, 72.7mmol) were added to the mixture, and the reaction mixture was stirred at 100 0 C for 4hours.
  • the reaction mixture was cooled to room temperature and filtrated through Celite. The residue was washed twice with DMF (6mL). Water (104mL) was added dropwise to the filtrate at room temperature over lOminutes. The mixture was stirred at room temperature for 15hours.
  • the aqueous layer was extracted with chloroform.
  • the organic layers were mixed and washed with saturated aqueous sodium chloride.
  • the resulting organic layer was dried over MgSO4.
  • Example 8 The compound obtained in Example 8 (743.2 mg, 3.08 mmol) was weighed in a reaction vessel. Subsequently, the atmosphere in the reaction vessel was replaced by nitrogen gas. THF (16 mL) was added to the reaction vessel, followed by dissolution at room temperature. Then, the compound 18 (800.7 mg, 2.93 mmol) and tosyl acid monohydrate (167.2 mg, 0.879 mmol) were added, followed by stirring for 30 min. The reaction mixture was ice- cooled and then sodium triacetoxyborohydride (3105 mg, 14.65 mmol) was added. Thereafter, the mixture was heated to room temperature and stirred for two hours and 45 minutes.
  • Example 9 The compound obtained in Example 9 (95.8 mg, purity: 63.0 wt%, 0.121 mmol, >98% ee) was dissolved in toluene (1.92 ml) and acetic acid (0.38 ml) at room temperature in a nitrogen atmosphere. Then, the solution was heated to 70 0 C and stirred for 13 hours. The reaction solution was air-cooled to room temperature. Thereafter, the reaction solution was quantitatively analyzed by the HPLC external standard method to determine the yield (yield: 63.9%). The optical purity was measured by chiral HPLC to be 39.3% ee.
  • Example 10 The compound obtained in Example 10 (56.9 mg, 0.114 mmol) was dissolved in toluene (1.14 ml) and acetic acid (0.23 ml) at room temperature in a nitrogen atmosphere. Then, the solution was heated to 80 0 C and stirred for 23.5 hours. Thereafter, the reaction solution was air-cooled to room temperature and concentrated under reduced pressure to obtain the title compound. The resulting crude product was quantitatively analyzed by the HPLC external standard method to determine the yield (yield: 95.1 %).
  • Triethylamine (6.5 ml) was added to the suspension of compound 4 (5.0 g), tris (dibenzylydeneacetone) dipalladium (856 mg), Tri(o-tolyl)phosphine (569 mg), methylacrylate (3.4 ml) in DMF (35 ml), and the mixture was stirred at 100 0 C for 55 minutes. The mixture was cooled to room temperature, and then passed through celite. The filtrate was concentrated under reduced pressure, and ethyl acetate (100 ml) and water (100ml) were added to the residue. The precipitated solids were removed by filtration with celite, and saturated sodium hydrogen carbonate (10 ml) was added to the filtrate.
  • the present invention can efficiently produce a 2-vinyl-5,6,7,8- tetrahydro[l,2,4]triazolo[l,5-a]pyridine derivative that has not yet been described in any documents, in particular, (8S)-2- ⁇ (E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2- yl]vinyl ⁇ -8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[l,2,4]triazolo[l,5-a]pyridine.

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Abstract

A compound represented by the formula (I): wherein A and B each represent an aryl group or a heteroaryl group which may have a substituent, or a salt thereof can be produced by heating a compound represented by the formula (II): wherein A and B are as defined above, in a solvent in the presence of an acid.

Description

DESCRIPTION
TITLE OF THE INVENTION: PROCESS FOR PRODUCING
TETRAHYDROTRIAZOLOPYRIDINE DERIVATIVE
TECHNICAL FIELD [0001]
The present invention relates to a process for producing a tetrahydrotriazolopyridine derivative. More particularly, the present invention relates to a process for producing a 2-vinyl-5,6,7,8-tetrahydro[l,2,4]triazolo[l,5-a]pyridine derivative represented by the formula (I): [Formula 1]
Figure imgf000002_0001
wherein A and B each represent an aryl group or a heteroaryl group which may have a substituent, and to a production intermediate thereof. Such a compound, in particular, (8S)-2- {(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-[2-
(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[l,2,4]triazolo[l,5-a]pyridine has an amyloid-β production reducing effect or the like and is useful as a progression inhibitor or a prophylactic agent for a disease involving amyloid-β such as Alzheimer's disease.
BACKGROUND ART [0002]
Alzheimer's disease is a disease characterized by degeneration and loss of neurons as well as formation of senile plaques and neurofibrillary degeneration. Currently, Alzheimer's disease is treated only with symptomatic treatment using a symptom improving agent typified by an acetylcholinesterase inhibitor, and a fundamental remedy to inhibit progression of the disease has not yet been developed. It is necessary to develop a method for controlling the cause of the onset of pathology in order to create a fundamental remedy for Alzheimer's disease.
It is assumed that Aβ-proteins such as amyloid-β 40 and amyloid-β 42 (hereinafter referred to as Aβ40 and Aβ42), which are metabolites of amyloid precursor proteins (hereinafter referred to as APP), are highly involved in degeneration and loss of neurons and onset of symptoms of dementia (see NON-PATENT DOCUMENTS 1 and 2, for example). Accordingly, a compound that reduces the production of Aβ40 and Aβ42 is expected as a progression inhibitor or prophylactic agent for Alzheimer's disease. [0003]
PATENT DOCUMENT 1 discloses the fact that a compound represented by the following formula: [Formula 2]
Figure imgf000003_0001
wherein U represents a nitrogen atom or the like, V represents an oxygen atom or the like, G represents an oxygen atom or the like, R1 represents a hydrogen atom, a halogen atom or the like, R2 represents a hydrogen atom, an alkyl group or the like, R5 represents an alkyl group or the like, R7 represents an alkyl group or the like, R8 represents a halogen atom or the like, R9 represents an alkyl group or the like and R10 represents an alkyl group or the like, is a γ-secretase modulator involved in the inhibition of production of Aβ40 and Aβ42, and also discloses a process for producing such a compound. [0004]
PATENT DOCUMENT 2 discloses the fact that a 2-[4-(imidazolyl)phenyl]vinyl- heterocycle derivative represented by the following formula: [Formula 3]
Figure imgf000003_0002
1 0 wherein R and R each 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, has an Aβ production inhibitory effect, and also discloses a process for producing such a compound. [0005] PATENT DOCUMENT 3 discloses the fact that a compound represented by the following formula: [Formula 4]
Figure imgf000004_0001
wherein Aη represents an imidazolyl group or the like which may be substituted with a Cl -6 alkyl group; Ar2 represents a phenyl group or the like which may be substituted with a C 1-6 alkoxy group; X1 represents a double bond or the like; and Het represents an imidazolyl group or the like which may be substituted with a Cl -6 alkyl group or the like, inhibits the production of amyloid-β 40 and 42 from amyloid precursor proteins, and also discloses a process for producing such a compound.
PRIOR ART DOCUMENT
PATENT DOCUMENT
[0006]
PATENT DOCUMENT 1: WO 2008/137139
PATENT DOCUMENT 2: WO 2008/097538 PATENT DOCUMENT 3: WO 2007/102580
[0007]
NON-PATENT DOCUMENT 1: Klein WL, et al., Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss,
Preceding National Academy of Science USA 2003, Sep 2; 100 (18), p. 10417-10422. NON-PATENT DOCUMENT 2: Nitsch RM, et al., Antibodies against β-amyloid slow cognitive decline in Alzheimer's disease, Neuron, 2003, May 22; 38, p. 547-554.
SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION [0008] The present inventors have found that novel compounds that have a chemical structure differing from those of the compounds described in PATENT DOCUMENTS 1 to 3 and have not yet been described in any documents, specifically, 2-vinyl-5,6,7,8- tetrahydro[l,2,4]triazolo[l,5-a]pyridine derivatives represented by the formula (I), in particular, a group of compounds typified by (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l- yl)pyridin-2-yl]vinyl}-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[l,2,4]triazolo[l,5- ajpyridine represented by the formula (1-3): [Formula 5]
Figure imgf000005_0001
have an effect of reducing the production of Aβ40 and Aβ42 (PCT/JP2007/054532).
A 2-[5-(imidazolyl)pyridin-2-yl]vinyl derivative represented by the formula (I), typically the formula (1-3), is a novel compound that has not yet been described in any documents. Therefore, a process for producing the same has not yet been known, and there is a need to develop an efficient process for producing the same. Accordingly, an object of the present invention is to provide a process for producing a 2-vinyl-5,6,7,8-tetrahydro[l,2,4]triazolo[l,5-a]pyridine derivative, in particular, (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-[2- (trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[l,2,4]triazolo[l,5-a]pyridine or a salt thereof, which has an amyloid-β production reducing effect, and to provide a production intermediate thereof and a process for producing the same.
MEANS FOR SOLVING THE PROBLEMS [0009]
As a result of extensive studies to achieve the above object, the present inventors have discovered the following production processes and production intermediates used for the processes. This has led to the completion of the present invention.
Specifically, the present invention relates to:
[I]. A process for producing a compound represented by the formula (I): [Formula 7]
Figure imgf000005_0002
( D wherein A represents an aryl group which may have 1 to 3 substituents selected from Substituent Group A or a heteroaryl group which may have 1 to 3 substituents selected from Substituent Group A; and B represents an aryl group which may have a substituent selected from Substituent Group B or a heteroaryl group which may have 1 to 3 substituents selected from Substituent Group A, or a salt thereof, the process comprising the step of: heating a compound represented by the formula (II): [Formula 6]
Figure imgf000006_0001
wherein A and B are as defined above, or a salt thereof in a solvent in the presence of an acid;
Substituent Group A: a halogen atom, a lower alkyl group having 1 to 6 carbon atoms which may have 1 to 3 substituents selected from Substituent Group Al, a lower alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 substituents selected from Substituent Group Al, an aryl group which may have 1 to 3 substituents selected from Substituent Group A2 and a heteroaryl group which may have 1 to 3 substituents selected from Substituent Group A2;
Substituent Group Al : a hydroxyl group, a halogen atom, a cyano group and a lower alkoxy group having 1 to 6 carbon atoms;
Substituent Group A2: a halogen atom and a lower alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms;
Substituent Group B: a halogen atom, a cyano group, a nitro group, a lower alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms and a lower alkoxy group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms;
[2]. The production process according to [1] above, wherein the process produces a compound represented by the formula (1-1) where A is the formula A2-Ai-:
[Formula 9]
Figure imgf000006_0002
( I - 1 ) wherein A1 represents an aryl group which may have 1 to 3 substituents selected from Substituent Group Al or a heteroaryl group which may have 1 to 3 substituents selected from Substituent Group Al; A2 represents an aryl group which may have 1 to 3 substituents selected from Substituent Group A2 or a heteroaryl group which may have 1 to 3 substituents selected from Substituent Group A2; and B is as defined in [1] above, or a salt thereof using a compound represented by the formula (II- 1): [Formula 8]
Figure imgf000007_0001
wherein A1, A2 and B are as defined above, or a salt thereof;
Substituent Group Al : a hydroxyl group, a halogen atom, a cyano group and a lower alkoxy group having 1 to 6 carbon atoms;
Substituent Group A2: a halogen atom and a lower alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms;
[3]. The production process according to [2] above, wherein A1 is a phenyl group which may have 1 to 3 substituents selected from Substituent Group Al or a pyridyl group which may have 1 to 3 substituents selected from Substituent Group Al;
[4]. The production process according to [2] above, wherein A2 is an imidazolyl group which may have 1 to 3 substituents selected from Substituent Group A2;
[5]. The production process according to any one of [1] to [4] above, wherein B is a phenyl group which may have a substituent selected from Substituent Group B; [6] . A process for producing 2- {(E)-2-[6-methoxy-5-(4-methyl- 1 H-imidazol- 1 -yl)pyridin-2- yl]vinyl}-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[l,2,4]triazolo[l,5-a]pyridine represented by the formula (1-2):
[Formula 11]
Figure imgf000007_0002
( I - 2 ) or a salt thereof, the process comprising the step of: heating (2E)-N'-{4-cyano-4-[2- (trifluoromethyl)phenyl]butyl}-3-[6-methoxy-5-(4-methyl- 1 H-imidazol- 1 -yl)pyridin-2- yl]acrylohydrazide represented by the formula (II-2): [Formula 10]
Figure imgf000008_0001
or a salt thereof in a solvent in the presence of an acid;
[7]. A process for producing (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2- yl]vinyl}-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[l,2,4]triazolo[l,5-a]pyridine represented by the formula (1-3): [Formula 15]
Figure imgf000008_0002
or a salt thereof, the process comprising the steps of: reacting (2S)-5-oxo-2-[2- (trifluoromethyl)phenyl]pentanenitrile represented by the formula (1): [Formula 12]
Figure imgf000008_0003
or a salt thereof with (2E)-3-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2- yl]acrylohydrazide represented by the formula (2): [Formula 13]
Figure imgf000009_0001
or a salt thereof to convert the compound of the formula (1) or the salt thereof to (2E)-N'- ((4S)- 4-cyano-4- [2-(trifluoromethyl)phenyl]butyl } -3 -[6-methoxy-5 -(4-methyl- 1 H-imidazol- 1 - yl)pyridin-2-yl]acrylohydrazide represented by the formula (II-3): [Formula 14]
Figure imgf000009_0002
or a salt thereof; and heating the compound of the formula (II-3) or the salt thereof in a solvent in the presence of an acid;
[8]. (2E)-N'-{(4S)-4-Cyano-4-[2-(trifluoromethyl)phenyl]butyl}-3-[6-methoxy-5-(4-methyl-lH- imidazol-1 -yl)pyridin-2-yl]acrylohydrazide represented by the formula (II-3): [Formula 16]
Figure imgf000009_0003
or a salt thereof;
[9]. A process for producing (2S)-5-oxo-2-[2-(trifluoromethyl)phenyl]pentanenitrile represented by the formula (1): [Formula 24]
Figure imgf000010_0001
or a salt thereof, the process comprising the steps of: reacting 2-trifluoromethylphenylacetic acid represented by the formula (3): [Formula 17]
Figure imgf000010_0002
or a salt thereof with (S)-(+)-4-phenyl-2-oxazolidinone represented by the formula (4): [Formula 18]
>sPh
ΓΛ
°ΎNH
0 ( 4 )
or a salt thereof to convert the compound of the formula (3) or the salt thereof to (4S)-4-phenyl- 3-{[2-(trifluoromethyl)phenyl]acetyl}-l,3-oxazolin-2-one represented by the formula (5): [Formula 19]
Figure imgf000010_0003
or a salt thereof; reacting the compound of the formula (5) or the salt thereof with l-chloro-3-iodopropane to convert the compound of the formula (5) or the salt thereof to (4S)-3-{(2S)-5-chloro-2-[2- (trifluoromethyl)phenyl]pentanoyl}-4-phenyl-l,3-oxazolin-2-one represented by the formula (6): [Formula 20]
Figure imgf000011_0001
or a salt thereof; hydrolyzing the compound of the formula (6) or the salt thereof to convert the compound of the formula (6) or the salt thereof to (2S)-5-chloro-2-[2-(trifluoromethyl)phenyl]pentanoic acid represented by the formula (7): [Formula 21]
Figure imgf000011_0002
or a salt thereof; converting the compound of the formula (7) or the salt thereof to (2S)-5-chloro-2-[2- (trifluoromethyl)phenyl]pentanoic acid amide represented by the formula (8): [Formula 22]
Figure imgf000011_0003
or a salt thereof; converting the compound of the formula (8) or the salt thereof to (2S)-5-chloro-2-[2-
(trifluoromethyl)phenyl]pentanenitrile represented by the formula (9): [Formula 23]
Figure imgf000012_0001
or a salt thereof; and reacting the compound of the formula (9) or the salt thereof; and [10]. A compound represented by the following formula: [Formula 25]
Figure imgf000012_0002
or a salt thereof.
ADVANTAGES OF THE INVENTION [0010]
The present invention can particularly produce a compound represented by the formula (1-3): [Formula 26]
Figure imgf000012_0003
or a salt thereof in a high yield. The present invention also provides a production intermediate for producing the compound of the formula (1-3) in a high yield and a process for producing the same. EMBODIMENT FOR CARRYING OUT THE INVENTION [0011]
Meanings of symbols, terms and the like used in the present specification will be explained below. [0012]
In the present specification, a structural formula of a compound may represent a certain isomer for convenience. However, the present invention includes all isomers and isomer mixtures such as geometric isomers which can be generated from the structure of a compound, optical isomers based on asymmetric carbon, stereoisomers and tautomers. The present invention is not limited to the description of a chemical formula for convenience and may include any one of the isomers or mixtures thereof. Accordingly, the compound of the present invention may have an asymmetric carbon atom in the molecule and exist as an optically active compound or racemate, and the present invention includes each of the optically active compound and the racemate without limitations. Although crystal polymorphs of the compound may be present, the compound is not limited thereto as well and may be present as a single crystal form or a mixture of single crystal forms. The compound may be an anhydride or a solvate such as a hydrate. [0013]
Any compound used in the production process of the present invention or any target compound produced by the process may be a salt. Specific examples of the salt include inorganic acid salts (such as sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, hydrofluorides, hydrochlorides, hydrobromides and hydroiodides), organic carboxylates (such as acetates, oxalates, maleates, tartrates, fumarates and citrates), organic sulfonates (such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates and camphorsulfonates), amino acid salts (such as aspartates and glutamates), quaternary amine salts, alkali metal salts (such as sodium salts and potassium salts) and alkali earth metal salts (such as magnesium salts and calcium salts). [0014]
The "aryl group" and "heteroaryl group" in the formulas (I) and (II) according to the present invention have the following meanings. [0015]
The "aryl group" refers to a monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring group having 6 to 14 carbon atoms, for example. Preferable examples of the group include 6- to 14-membered monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring groups such as a phenyl group, an indenyl group, a naphthyl group, an azulenyl group, a heptalenyl group, a biphenyl group, a fluorenyl group, a phenalenyl group, a phenanthrenyl group and an anthracenyl group. Among these, a phenyl group is preferable, for example. [0016] The "heteroaryl group" refers to a monocyclic, bicyclic or tricyclic aromatic heterocyclic group having 5 to 14 carbon atoms. Preferable examples of the group include (1) nitrogen-containing aromatic heterocyclic groups such as a pyrrolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a pyrazolinyl group, an imidazolyl group, an indolyl group, an isoindolyl group, an indolizinyl group, a purinyl group, an indazolyl group, a quinolyl group, an isoquinolyl group, a quinolizinyl group, a phthalazinyl group, a naphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a pteridinyl group, an imidazotriazinyl group, a pyrazinopyridazinyl group, an acridinyl group, a phenanthridinyl group, a carbazolyl group, a perimidinyl group, a phenanthrolinyl group and a phenacyl group, (2) sulfur-containing aromatic heterocyclic groups such as a thienyl group and a benzothienyl group, (3) oxygen-containing aromatic heterocyclic groups such as a furyl group, a pyranyl group, a cyclopentapyranyl group, a benzofuranyl group and an isobenzofuranyl group and (4) aromatic heterocyclic groups containing two or more hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom such as a thiazolyl group, an isothiazolyl group, a benzothiazolinyl group, a benzothiadiazolyl group, a phenothiazinyl group, an isoxazolyl group, a furazanyl group, a phenoxazinyl group, a pyrazoloxazolyl group, an imidazothiazolyl group, a thienofuryl group, a furopyrrolyl group and a pyridooxazinyl group. Among these, a thienyl group, an imidazolyl group and a pyridyl group are preferable, for example. [0017] The "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like and is preferably a fluorine atom, a chlorine atom or a bromine atom. [0018]
Preferable examples of the "lower alkyl group having 1 to 6 carbon atoms" include linear or branched alkyl groups such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a tert-butyl group, an n-pentyl group, an i-pentyl group, a neopentyl group, an n-hexyl group, a 1-methylpropyl group, an 1,2- dimethylpropyl group, a 1-ethylpropyl group, a l-methyl-2-ethylpropyl group, a l-ethyl-2- methylpropyl group, a 1,1,2-trimethylpropyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 2-ethylbutyl group, a 1,3- dimethylbutyl group, a 2-methylpentyl group and a 3-methylpentyl group. [0019]
The "lower alkoxy group having 1 to 6 carbon atoms" refers to an alkyl group having 1 to 6 carbon atoms in which a hydrogen atom is replaced by an oxygen atom. Preferable examples of the group include a methoxy group, an ethoxy group, an n-propoxy group, an i- propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentoxy group, an i-pentoxy group, a sec-pentoxy group, a tert-pentoxy group, an n-hexoxy group, an i-hexoxy group, a 1,2-dimethylpropoxy group, a 2-ethylpropoxy group, a l-methyl-2- ethylpropoxy group, a l-ethyl-2-methylpropoxy group, a 1,1,2-trimethylpropoxy group, a 1,1,2- trimethylpropoxy group, a 1,1-dimethylbutoxy group, a 2,2-dimethylbutoxy group, a 2- ethylbutoxy group, a 1,3-dimethylbutoxy group, a 2-methylpentoxy group, a 3-methylpentoxy group and a hexyloxy group.
[0020]
The "lower alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms" refers to a lower alkyl group in which a hydrogen atom in the aforementioned lower alkyl group may be replaced by a halogen atom. Examples of the group include a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trichloromethyl group, a 1,2-difluoroethyl group, a 2,2-difluoroethyl group, a 1,2-dichloroethyl group, a 1,2-difluoropropyl group and a 2,2-difluoropropyl group. [0021]
The "lower alkoxy group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms" refers to a lower alkoxy group in which a hydrogen atom in the aforementioned lower alkoxy group may be replaced by a halogen atom. Examples of the group include a monofluoromethyloxy group, a difluoromethyloxy group, a trifluoromethyloxy group and a trichloromethyloxy group. [0022]
The "Substituent Group A", "Substituent Group Al", "Substituent Group A2" and "Substituent Group B" in the formulas (I) and (II) according to the present invention have the following meanings: Substituent Group A: a halogen atom, a lower alkyl group having 1 to 6 carbon atoms which may have 1 to 3 substituents selected from Substituent Group Al, a lower alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 substituents selected from Substituent Group Al, an aryl group which may have 1 to 3 substituents selected from Substituent Group A2 and a heteroaryl group which may have 1 to 3 substituents selected from Substituent Group A2; Substituent Group Al : a hydroxyl group, a halogen atom, a cyano group and a lower alkoxy group having 1 to 6 carbon atoms;
Substituent Group A2: a halogen atom and a lower alkyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms; and Substituent Group B: a halogen atom, a cyano group, a nitro group, a lower alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms and a lower alkoxy group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms. [0023] The present invention will be described in detail below.
[0024]
Production Process 1 [Formula 27]
Figure imgf000016_0001
( I I ) ( I )
In the formula, A and B are as defined above. [0025]
Production Process 1 is a process for producing a compound (I) from a compound (II) as a raw material. [0026] Step l Step 1 is a step of heating an N'-(4-cyanobutyl)acrylohydrazide derivative represented by the formula (II) in a solvent in the presence of an acid to cause intramolecular cyclization reaction to convert the compound (II) to a 2-vinyl-5,6,7,8- tetrahydro[l,2,4]triazolo[l,5-a]pyridine derivative represented by the formula (I) (hereinafter Step 1). [0027]
The compound of the formula (II) can be produced from a commercially available product by a method known to a person skilled in the art according to a production process described later in Production Processes 2, 4, 5 and 6 or Examples. Specifically, for example, a compound (II-3) of the formula (II), wherein A is a 6-methoxy-5-(4-methyl-lH-imidazol-l- yl)pyridine-2-yl group and B is a 2-(trifluoromethyl)phenyl group, can be produced by producing a compound (9) from a compound (6) as shown in the later-described Production Process 5; further producing a compound (1) from the compound (9) as shown in Production Process 4; separately producing a compound (2) from a compound (13) as shown in Production Process 6; and then reacting the compound (1) with the compound (2) as shown in Production Process 2. The compound of the formula (II), wherein A and B are other functional groups, can be produced by producing a compound corresponding to the compound (1) by the same method as shown in Production Processes 5 and 4 using a compound in which the 2-(trifluoromethyl)phenyl group in the compound (6) of Preparation Process 5 is replaced by the other functional group B; separately producing a compound corresponding to the compound (2) by the same method as shown in Production Process 6 using a compound in which the 6-methoxy-5-(4-methyl-lH- imidazol-l-yl)pyridin-2-yl group in the compound (13) of Preparation Process 6 is replaced by the other functional group A; and reacting this compound with the compound corresponding to the compound (1) in the same manner as in Step 2-1 of Production Process 2. [0028]
The reaction in Step 1 is performed out using an acid such as acetic acid. The solvent used in this reaction is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent. Tetrahydrofuran, benzene, toluene or N,N-dimethylformamide may be used, for example. The reaction temperature is not particularly limited and is usually room temperature to 1000C. [0029]
In Step 1, it is preferable to produce a compound represented by the formula (1-1) where A is the formula A2-Ai-: [Formula 29]
Figure imgf000017_0001
wherein Ai, A2 and B are as defined above, using, as the compound (II), a compound represented by the formula (II- 1): [Formula 28]
Figure imgf000018_0001
wherein A1, A2 and B are as defined above.
[0030]
Production Process 2 [Formula 30]
Figure imgf000018_0002
[0031]
Production Process 2 is a process for producing a compound (1-3) from a compound (2) as a raw material. A compound (II-3) is a novel compound that has not yet been described in any documents. [0032] Step 2-1
Step 2-1 is a step of obtaining a compound (II-3) by reductive animation reaction of a compound (1) with a compound (2).
This reaction can be performed under the same conditions as those usually used in reductive animation reaction of a carbonyl compound with an amine compound. The reduction reaction used in this reaction is not particularly limited. Examples of the reduction reaction include reductive animation reaction using a reducing agent such as borane, a boron hydride complex compound or formic acid; and catalytic reduction reaction using a metal catalyst in a hydrogen atmosphere. Examples of the reductive animation reaction using a boron hydride complex compound include reactions according to documents such as W.S. Emerson, Organic Reactions, 4, 174 (1948); CF. Lane, Synthesis, 135 (1975); J.C. Stowell and SJ. Pedegimas, Synthesis, 127 (1974); and A.F. Abdel-Magid, K.G. Carson, B.D. Harris, CA. Maryanoff, and R.D. Shah, Journal of Organic Chemistry, 61, 3849 (1996).
The compound (2) used may be a free form or a salt. A hydrochloride, a hydrobromide or the like of the compound (2) can be preferably used.
Examples of the boron hydride complex compound that can be used include sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride. When the boron hydride complex compound is used as a reducing agent, the solvent is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent. Specific examples of the solvent that can be used include methanol, ethanol, tetrahydrofuran, dichloromethane and 1,2-dichloroethane. More preferable results such as an improved yield can be achieved by performing this reaction in the presence of an acid. Such an acid is not particularly limited. Preferable examples of the acid include mineral acids such as hydrochloric acid, organic acids such as acetic acid, and Lewis acids such as zinc chloride, a boron trifluoride-diethyl ether complex and titanium (IV) tetraisopropoxide. The reaction temperature is not particularly limited and is usually -78°C to solvent reflux temperature, and preferably ice-cold temperature to room temperature. When formic acid is used as a reducing agent, the solvent is not particularly limited insofar as it does not inhibit the reaction. An excess of formic acid may be used as a solvent. The reaction temperature is not particularly limited and is usually 500C to solvent reflux temperature. Heating to a high temperature of 150 to 2500C by use of a sealed pressure vessel may provide excellent results such as a reduced reaction time. The solvent used in the catalytic reduction reaction in a hydrogen atmosphere is not particularly limited insofar as it does not inhibit the reaction. Examples of the solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane and ethyl acetate. Examples of the metal catalyst used in the reaction include palladium-carbon, palladium hydroxide-carbon, platinum oxide and Raney nickel. The reaction conditions are not particularly limited, and the reaction can be performed at room temperature to solvent reflux temperature and at normal pressure to 150 atm, and preferably at room temperature to 600C and at normal pressure to 5 atm. More preferable results such as an improved yield can be achieved by performing this reaction in the presence of an acid. Such an acid is not particularly limited. Preferable examples of the acid include mineral acids such as hydrochloric acid and organic acids such as acetic acid. [0033]
Step 2-2 is a step of heating the compound (II-3) in a solvent to cause intramolecular cyclization reaction to convert the compound (II-3) to a compound (1-3).
The reaction may be performed under acidic, neutral or basic conditions and is preferably performed using an acid such as acetic acid. The solvent used in the reaction is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent. Tetrahydrofuran, benzene, toluene or N5N- dimethylformamide may be used, for example. The reaction temperature is not particularly limited and is usually 500C to 1000C. [0034]
Production Process 3 [Formula 31]
Figure imgf000020_0001
[0035]
Production Process 3 is a process alternative to the aforementioned Production Process 2 to produce a compound (1-3) and is a process for producing a compound (1-3) by reacting a compound (10) with a compound (11). [0036] Step 3
Step 3 is a step of obtaining a compound (1-3) by condensation cyclization of a compound (10) (2-imino-3-[2-(trifluoromethyl)phenyl]piperidin-l-amine) with a compound (11) ((2E)-3-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]acrylic acid).
A method of activating a carboxylic acid moiety is effective for this reaction. Examples of the method include an acid chloride method, a method using a carbodiimide condensing agent and a method using a phosphoryl azide condensing agent. The solvent used in the reaction is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent. Tetrahydrofuran, benzene, toluene or N,N-dimethylformamide may be used, for example. The reaction temperature is not particularly limited and is usually 500C to 1000C.
The compound (10) can be produced from a commercially available product by a method known to a person skilled in the art according to a production process described later in Production Process 4 or Examples. The compound (11) can be produced from a commercially available product by a method known to a person skilled in the art according to a production process described later in Production Process 6.
The compound (10) used may be a free form or a salt. A hydrochloride, a hydrobromide or the like of the compound (10) can be preferably used. [0037] Production Process 4 [Formula 32]
Figure imgf000021_0001
( 9 ) ( 1 )
Step 4-2
Figure imgf000021_0002
[0038]
Production Process 4 is a process for producing a compound (1) and a compound (10) from a compound (9) as a raw material. The compound (1) and the compound (9) are novel compounds that have not yet been described in any documents. [0039] Step 4-1
Step 4-1 is a step of obtaining a compound (1) from a compound (9) by oxidation reaction.
This reaction is a reaction of converting a methyl halide to an aldehyde by oxidation reaction. Examples of the oxidizing agent used in the reaction include DMSO (Kornblum oxidation), nitro compounds (Haas reaction), hexamine (Sommelet reaction), p- nitrosodimethylaniline (Krohnke reaction) and amine oxides. For example, when DMSO (Kornblum oxidation) is used for a methyl halide compound having low reactivity, it is necessary to convert the compound to an iodo compound first and heat the iodo compound together with DMSO in the presence of a base such as sodium bicarbonate, triethylamine or collidine (see H.C. Brown, J.S. Cha, N.M. Yoon and B. Nazer, J. Org. Chem., 52, 5400 (1987)). The iodo compound may be either isolated or used for the reaction in one pot without isolation. This reaction may be performed under highly mild conditions when a silver salt such as silver tetrafluoroborate is added (see J.S. Cha, J.E. Kim and K. W. Lee, J. Org. Chem., 52, 5030 (1987)). [0040] Step 4-2 Step 4-2 is a step of converting a nitrile compound (9) to an imidate compound
(12).
The imidate compound obtained in this reaction can be synthesized by the Pinner method in which an alcohol is added to a nitrile in the presence of hydrogen chloride or by a method of adding an alcohol to a nitrile in the presence of a base (see P. Raynaud, R.C. Moreau, Bull. Soc. Chem. Fr., 1964, 2997 or A. W. Dox, Org. Synth., I, 5 (1941), for example). [0041] Step 4-3
Step 4-3 is a step of obtaining a compound (10) from the compound (12). In this reaction, the imidate compound (12) can be converted to a compound (10) by reaction with hydrazine and intramolecular cyclization.
The compound (9) can be produced from a commercially available product by a method known to a person skilled in the art according to a production process described later in Production Process 5 or Examples. [0042]
Production Process 5
[Formula 33]
Figure imgf000023_0001
( 6 ) ( 7 )
Figure imgf000023_0002
( 8 ) ( 9 )
[0043] Production Process 5 is a process for producing a compound (9) from a compound
(6) as a raw material. The compound (7) and the compound (8) are novel compounds that have not yet been described in any documents. [0044] Step 5-1 Step 5-1 is a step of obtaining a compound (7) from a compound (6) by oxidative hydrolysis.
This reaction is not particularly limited insofar as the conditions are similar to those in this reaction. A known method described in many documents (such as described in Evans, D.A.; Bartroli, J.; Shih, T.I., J. Am. Chem. Soc, 1981, 103, 2127-2129) may be used. Specifically, in the reaction, an acyloxazolidinone compound is reacted with hydrogen peroxide and an alkali hydroxide such as lithium hydroxide in a water-miscible solvent such as tetrahydrofuran in the presence of water to convert the compound to carboxylic acid.
The reaction temperature is preferably O0C to room temperature. [0045] Step 5-2
Step 5-2 is a step of converting the carboxylic acid (7) to an amide (8). This reaction of converting carboxylic acid to amide is not particularly limited insofar as the conditions are similar to those in this reaction. A known method described in many documents (such as described in Jikken Kagaku Koza (Courses in Experimental Chemistry), 4th edition, 22, Maruzen Co., Ltd., 1992, p. 138-144) may be used.
Well-known methods for converting carboxylic acid to amide are 1) a method using dehydration by heating and 2) a method using a condensing agent. [0046] Step 5-3
Step 5-3 is a step of converting the amide compound (8) to a nitrile compound (9) by dehydration.
This reaction is not particularly limited insofar as the conditions are similar to those in this reaction. A known method described in many documents (such as described in Jikken Kagaku Koza (Courses in Experimental Chemistry), 4th edition, 20, Maruzen Co., Ltd., 1992, p. 449-450) may be used.
Examples of the dehydrating agent used in this reaction include phosphorus pentoxide, phosphorus pentachloride, thionyl chloride, toluenesulfonyl chloride, methanesulfonyl chloride, chlorosulfonyl cyanate, N,N-dicyclohexylcarbodiimide and 2- chlorobenzoxazolium salts.
This reaction is performed by a method using a solvent or by a method of distilling a reaction mixture by directly heating without a solvent.
The solvent used in the method using a solvent is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent. Preferable examples of the solvent include acetonitrile, tetrahydrofuran, 1,4- dioxane, 1 ,2-dimethoxyethane, benzene, toluene, xylene, l-methyl-2-pyrrolidone and N,N- dimethylformamide.
The compound (6) can be produced from a commercially available product by a method known to a person skilled in the art according to a production process described later in Examples. [0047]
Production Process 6
[Formula 34]
Figure imgf000025_0001
Step 6-2 Step 6-1
Figure imgf000025_0002
[0048] Production Process 6 is a process for producing a compound (2) or a compound
(11) from a compound (13) as a raw material. [0049] Step 6-1
Step 4-1 is a step of obtaining a compound (16) or a compound (17) by Mizoroki- Heck reaction of a compound (13) with a compound (14) or a compound (15). [0050]
In Mizoroki-Heck reaction, a halogen compound or triflate compound (13), wherein X represents a chlorine atom, a bromine atom, an iodine atom or a sulfonate group such as a trifluoromethanesulfonate group, is preferably coupled with 1.0 to 5.0 equivalents of an alkene compound (14) or (15) with respect to the compound (13) in the presence of 0.01 to 0.2 equivalent of a transition metal catalyst with respect to the compound (13), for example. This reaction is preferably performed in the presence of a solvent from the viewpoint of handleability and stirring efficiency. The solvent used varies according to the starting material and the transition metal catalyst used, and is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent. Preferable examples of the solvent include acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, l-methyl-2-pyrrolidone and N,N-dimethylformamide. The reaction temperature must be a temperature that can complete the coupling reaction, and is preferably room temperature to 150°C. This reaction is performed preferably in an inert gas atmosphere, and more preferably in a nitrogen or argon atmosphere. The transition metal catalyst is preferably a palladium complex, for example, and more preferably a known palladium complex such as palladium (II) acetate, dichlorobis(triphenylphosphine)palladium (II), tetrakis(triphenylphosphine)palladium (0) or tris(dibenzylideneacetone)dipalladium (0). It is also preferable to appropriately add a phosphorus ligand (preferably triphenylphosphine, tri-o- tolylphosphine, tri-tert-butylphosphine or 2-(di-tert-butylphosphino)biphenyl, for example) in order to make the reaction efficiently proceed. A preferable result may be achieved in the presence of a base. The base used is not particularly limited insofar as it is used in a coupling reaction similar to this reaction. Preferable examples of the base include triethylamine, N5N- diisopropylethylamine, N,N-dicyclohexylmethylamine and tetrabutylammonium chloride. [0051] Step 6-2
Step 6-2 is a step of obtaining a compound (2) from the compound (16) by deprotection reaction.
This deprotection reaction varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction. A known method described in many documents may be used for the reaction (see T. W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., 1999, p. 615-626). Preferably, a compound having a tert-butyl carbamate group as a protecting group is stirred in a solvent in the presence of 1.0 to 100.0 equivalents of an acid with respect to the compound, for example. Examples of the acid used include inorganic acids such as hydrochloric acid and sulfuric acid; and organic acids such as trifluoroacetic acid and methanesulfonic acid. The solvent used is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent. Preferable examples of the solvent include ethyl acetate, methanol, ethanol, 1,4-dioxane, methylene chloride, chloroform, methanol, isopropyl alcohol, N,N-dimethylformamide and N-methylpyrrolidone. The reaction temperature must be a temperature that can complete the reaction without promoting formation of an undesirable byproduct, and is preferably 0 to 1000C, for example. [0052] Step 6-3 Step 6-3 is a step of obtaining a compound (11) from the ester compound (17) by hydrolysis reaction. [0053]
The carboxylic acid compound (11) is prepared by hydrolysis of the ester compound (17). Specifically, Step 6-3 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction. A known method described in many documents may be used for the reaction (see Shin Jikken Kagaku Koza (New Courses in Experimental Chemistry), vol.22, Yuki Gosei (Organic Synthesis) [IV], edited by The Chemical Society of Japan, Maruzen Co., Ltd., November 1992, p.6-11, for example). Preferably, an ester compound (8) is stirred in a solvent in the presence of 1.0 to 100.0 equivalents of a base or acid with respect to the ester compound (8), for example. The base used varies according to the starting material and is not particularly limited. Preferable examples of the base include sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate and barium carbonate. The acid used varies according to the starting material and is not particularly limited. Preferable examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid; organic acids such as trifluoroacetic acid and p-toluenesulfonic acid; and Lewis acids such as boron trichloride. The solvent used varies according to the starting material, and is not particularly limited insofar as it does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent. Preferable examples of the solvent include alcohol solvents such as methanol, ethanol and ethylene glycol; ether solvents such as tetrahydrofuran; water; and mixed solvents thereof.
In the case of acid hydrolysis, an organic acid such as acetic acid or formic acid may be used as a solvent. The reaction temperature must be a temperature that can complete the reaction without promoting formation of an undesirable by-product, and is preferably room temperature to 1000C, for example.
[0054]
The present invention will now be described in detail with reference to examples; however, the examples are provided only for illustration purposes. The production process of the present invention is not limited to the following specific examples in any cases. A person skilled in the art can fully implement the present invention by making various modifications to not only the following examples but also the claims of the present specification, and such modifications are within the scope of the claims of the present specification.
The abbreviations used in Examples are conventional abbreviations known to a person skilled in the art. Some abbreviations are shown below. [0055]
THF: Tetrahydrofuran
DMF: N,N-Dimethylformamide
DMSO: Dimethyl sulfoxide
MTBE: tert-Butyl methyl ether TFA: Trifluoroacetic acid
DMPU: 1 ,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone
EDC HCl: l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
HOBt: 1-Hydroxybenzotriazole
LHMDS: Lithium Hexamethyldisilazide pTLC: Preparative thin-layer chromatography
LC-MS: Liquid chromatography-mass spectrometry
PyBOP: Benzotriazol-l-yloxytris(pyrrolidino)phosphonium hexafluorophosphate
Pd2DB A3 : Tris(dibenzylideneacetone)dipalladium
Pd(t-Bu3P)2: Bis(tri-t-butylρhosρhine)palladium [0056]
Chemical shifts in proton nuclear magnetic resonance spectra are recorded in δ units (ppm) relative to tetramethylsilane and coupling constants are recorded in Hertz (Hz).
Patterns are designated as s: singlet, d: doublet, t: triplet, q: quartet, br: broad.
[0057] The "room temperature" in the following Examples and Preparation Examples typically refers to about 10°C to about 35°C. "%" indicates wt% unless otherwise specified. Example 1 [0058] Synthesis of (4S)-4-phenyl-3-{[2-(trifluoromethyl)phenyllacetvU-l,3-oxazolin-2-one [Formula 35]
Figure imgf000029_0001
[0059]
Triethylamine (51.5 mL, 368 mmol) was added to a suspension of 2- trifluoromethylphenylacetic acid (37.6 g, 184 mmol) and (s)-(+)-4-phenyl-2-oxazolidinone (15 g, 92 mmol) in toluene (450 mL) at room temperature. Pivaloyl chloride (22.7 mL, 184 mmol) was added dropwise to the suspension with stirring at room temperature. The resulting suspension was heated under reflux with stirring for 18 hours. After cooling to room temperature, 2 N hydrochloric acid (150 mL) was added, followed by extraction. The organic layer was sequentially washed with a saturated sodium bicarbonate solution (150 mL) twice, a 5% sodium chloride solution (150 mL) and water (150 mL) and concentrated under reduced pressure. Ethyl acetate (45 mL) was added to the resulting solid, and the solid was completely dissolved by heating to 5O0C. Heptane (180 mL) was added to the solution, followed by gradually cooling to room temperature. The resulting suspension was further cooled to ice-cold temperature, and then filtered, washed with heptane (150 mL) and dried under reduced pressure to obtain 27.7 g (content: 93%) of first crystals of the title compound. From the filtrate, 1.43 g (content: 87%) of second crystals were obtained. The crystals were combined to obtain the title compound as white crystals in a yield of 84%.
1H-NMR (400 MHz, CDCl3): δ 4.34 (dd, J = 4.0, 8.8 Hz, IH), 4.47 (s, 2H), 4.76 (dd, J = 8.8, 9.2 Hz, IH), 5.44 (dd, J = 3.6, 8.8 Hz, IH), 7.21 (d, J = 7.6 Hz, IH), 7.26-7.40 (m, 6H), 7.46 (dd, J = 7.6, 7.6 Hz, IH), 7.62 (d, J = 8.0 Hz, IH). Example 2 [0060]
Synthesis of (4SV3-((2S)-5-chloro-2-r2-(trifluorόmethvπphenyllpentanovU-4-phenyl-L3- oxazolin-2-one [Formula 36]
Figure imgf000030_0001
[0061]
LHMDS (1 M solution in THF, 94.3 mL, 94.3 mmol) was added dropwise to a solution of the compound of Example 1 (27.5 g, 78.7 mmol) in THF (275 mL) at -15°C. 1- Chloro-3-iodopropane (33 mL, 315 mmol) and DMPU (94.8 mL, 787 mmol) were added dropwise thereto at -15°C. The mixture was stirred at -150C for 23 hours and at 00C for 15 hours, followed by addition of a 5% sodium chloride solution (275 mL) and MTBE (275 mL). The organic layer was washed with a 5% sodium chloride solution (275 mL) and concentrated under reduced pressure. The residue was extracted with a mixture of MTBE (140 mL) and heptane (140 mL) and with water. The organic layer was concentrated under reduced pressure and then azeotropically distilled with MTBE (55 mL) twice. Ethanol (83 mL) was added to the residue, followed by heating to 500C. After confirming the formation of a homogeneous solution, a small amount of seed crystals were added. After one hour at room temperature, filtration was performed. The crystals were washed with cold ethanol (15 mL) and dried under reduced pressure to obtain 17.5 g of the title compound (content: 92%, 94.6% de) in a yield of 51.3%.
Ethanol (48 mL) was added to the resulting title compound (content: 92%, 16 g, 34.6 mmol), and the compound was completely dissolved by heating to 500C. The solution was gradually cooled to room temperature. The generated crystals were washed with cold ethanol (15 mL) and dried under reduced pressure to obtain 14.9 g of the title compound (content: 96.3%, 100% de) in a yield of 97.8%.
1H-NMR (400 MHz, CDCl3): δ 1.64-1.72 (m, IH), 1.74-1.84 (m, IH), 1.98-2.09 (m, IH), 2.12- 2.23 (m, IH), 3.44-3.53 (m, 2H), 4.31 (dd, J = 3.2, 8.8 Hz, IH), 4.68 (dd, J = 8.8, 8.8 Hz, IH), 5.36 (dd, J = 3.2, 8.8 Hz, IH), 5.54 (dd, J = 4.8, 9.2 Hz, IH), 7.28-7.34 (m, 2H), 7.35-7.46 (m, 4H), 7.52-7.59 (m, 1 H), 7.60-7.68 (m, 2H). Example 3 [0062] Synthesis of (2S)-5-chloro-2-r2-(trifluoromethyl)phenvnpentanoic acid [Formula 37]
Figure imgf000031_0001
[0063]
The compound obtained in Example 2 (4000 mg, 9.09 mmol) was weighed in a reaction vessel. Subsequently, the atmosphere in the reaction vessel was replaced by nitrogen gas. Tetrahydrofuran (40 ml) and water (20 ml) were added to the reaction vessel. After dissolution at room temperature, a 30% hydrogen peroxide solution (1.24 mL, 1.2 eq) was added dropwise at 00C. Lithium hydroxide monohydrate (458 mg, 10.91 mmol) was further added, followed by stirring at that temperature for 45 minutes. A 10% sodium thiosulfate pentahydrate solution (48 mL) was added to the reaction solution, followed by stirring. The reaction was terminated, followed by addition of ethyl acetate (100 mL). Subsequently, the mixture was adjusted to pH 1 to 2 with 5 N hydrochloric acid (about 2 mL), and then the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 10% saline twice. The resulting crude product was purified by NH silica gel chromatography (eluent: methanol/acetic acid = 10/1). The purified product was azeotropically distilled with toluene five times and acetic acid was removed to obtain the title compound as a toluene mixture (2692 mg, purity: 87.4 wt%). Yield: 92.3%
1H-NMR (400 MHz, CDCl3): δ 7.68 (d, J = 7.6 Hz, IH), 7.61-7.52 (m, 2H), 7.39 (t, J = 7.6 Hz, IH), 4.08 (t, J = 7.6 Hz, IH), 3.52 (t, J = 6.4 Hz, 2H), 2.31-2.20 (m, IH), 2.05-1.80 (m, 2H), 1.74-1.62 (m, IH) Example 4 [0064]
Synthesis of (2S)-5-chloro-2-[2-(trifluoromethyl)phenyl]pentanoic acid amide [Formula 38]
Figure imgf000031_0002
[0065] The compound obtained in Example 3 (2.596 g, purity: 87.4 wt%, 8.08 mmol) was weighed in a reaction vessel. Subsequently, the atmosphere in the reaction vessel was replaced by nitrogen gas. DMF (46 mL) was added to the reaction vessel, followed by dissolution at room temperature. Then, ammonium chloride (2161 mg, 40.4 mmol, 5 eq), diisopropylethylamide (13 mL, 74.6 mmol, 9.2 eq), HOBt (1324 mg, 9.80 mmol) were added, respectively. PyBOP (5097 mg, 9.80 mmol) was further added, followed by stirring at room temperature for 10.5 hours. H2O and ethyl acetate were added to the reaction mixture, followed by stirring. Then, the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water. The resulting crude product was purified by Silica gel chromatography (eluent: heptane/ethyl acetate = 4/1 -> 2/1) and then purified again by NH silica gel chromatography (eluent: ethyl acetate) to obtain the title compound (2170 mg, 92.3 wt%, >99% ee). Yield: 88.6%
1H-NMR (400 MHz, CDCl3): δ 7.69 (d, J = 7.6 Hz, IH), 7.66 (d, J = 7.6 Hz, IH), 7.56 (t, J = 7.6 Hz, IH), 7.38 (t, J = 7.6 Hz, IH), 5.36 (brd, J = 24 Hz, 2H), 3.82 (t, J = 6.8 Hz, IH), 3.57-3.42 (m, 2H), 2.35-2.22 (m, IH), 1.98-1.80 (m, 2H), 1.67-1.52 (m, IH) Example 5 [0066]
Synthesis of (2S)-5-chloro-2-f2-(trifluoromethyl)phenyllpentanenitrile [Formula 39]
Figure imgf000032_0001
[0067]
The compound obtained in Example 4 (2059 mg, 7.36 mmol) was weighed in a reaction vessel. Subsequently, the atmosphere in the reaction vessel was replaced by nitrogen gas. DMF (16 mL) was added to the reaction vessel, followed by dissolution at room temperature. Then, toluene (33 mL) was added. After cooling to -35°C, thionyl chloride (1073 μL, 14.72 mmol, 2 eq) was added dropwise, followed by stirring for 1.5 hours.
The mixture was heated to -200C and then stirred for 20 minutes. Further, the mixture was heated to -150C and then stirred for 40 minutes. Ice water (about 30 mL) was introduced into the reaction mixture and the reaction was terminated. Thereafter, ethyl acetate (50 mL) was introduced, followed by stirring. The organic layer was then separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 10% aqueous sodium bicarbonate and 10% saline. The resulting crude product was further washed with water and then dried over magnesium sulfate. Magnesium sulfate was removed by filtration. The resulting mixture was concentrated to obtain the title compound (2105 mg, 88.06 wt%, >99% ee). Yield: 96.3%
1H-NMR (400 MHz, CDCl3): δ 7.71 (m, 2H), 7.65 (t, J = 7.6 Hz, IH), 7.47 (t, J = 7.6 Hz, IH), 4.18 (m, IH), 3.58 (m, 2H), 2.18-1.88 (m, 4H) Example 6 [0068]
Synthesis of (2S)-5-oxo-2-[2-(trifluoromethyl)phenyl]pentanenitrile [Formula 40]
Figure imgf000033_0001
[0069] The compound obtained in Example 6 (1892 mg, 7.23 mmol) was weighed in a reaction vessel. Subsequently, the atmosphere in the reaction vessel was replaced by nitrogen gas. DMSO (20 mL) was added to the reaction vessel, followed by dissolution at room temperature. Then, 2,4,6-collidine (1528 μL, 11.6 mmol) and sodium iodide (3492 mg, 23.3 mmol) were added. The mixture was heated at 800C for 15 hours and cooled to room temperature. Water and ethyl acetate were introduced into the reaction mixture, and then the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 0.5 N hydrochloric acid and then washed with 10% saline and with water twice. The resulting organic layer was concentrated and then purified by silica gel chromatography (eluent: heptane/ethyl acetate = 6/1 -> 5/1 -> 4/1 -> 2/1) to obtain the title compound (757.5 mg, 3.14 mmol, >99% ee, yield: 43%).
1H-NMR (400 MHz, CDCl3): δ 9.79 (s, IH), 7.70 (m, 2H), 7.64 (m, IH), 7.48 (m, IH), 4.25 (dd, J = 8.8, 6.8 Hz, IH), 2.84-2.66 (m, 2H), 2.29-2.19 (m, 2H)
Example 7 [0070] Synthesis of /ert-Butyl 2-U2EV3-r6-methoxy-5-r4-methyl-lH-imidazol-l-vπpyridin-2-yllprop- 2-enoyl I hvdrazinecarboxylate [Formula 41]
Figure imgf000034_0001
[0071]
DMF (52mL) was added to 6-Bromo-2-methoxy-3-(4-methyl-lH-irnidazol-l- yl)pyridine (13.0g, 48.5mmol) and the tert-Butyl 2-acryloylhydrazinecarboxylate (9.9g, 53.3mmol) at room temperature under nitrogen atmosphere, And the mixture was stirred at 500C for lOminutes. Tri(o-tolyl)phosphine (885mg, 2.90mmol), Palladium (II) acetate (327mg, 1.45mmol) and N,N-diisopropylethylamine (12.7mL, 72.7mmol) were added to the mixture, and the reaction mixture was stirred at 1000C for 4hours. The reaction mixture was cooled to room temperature and filtrated through Celite. The residue was washed twice with DMF (6mL). Water (104mL) was added dropwise to the filtrate at room temperature over lOminutes. The mixture was stirred at room temperature for 15hours. After the mixture was filtrated, the residue was washed with water/DMF =2: 1(3OmL) and MTBE (3OmL). The obtained solid was suspended in MTBE (5OmL) at room temperature for 2hours, filtrated and dried under the reduced pressure to obtain the title compound (15.8g, 87% yield). 1H-NMR (400MHz, CDCl3) δ (ppm):1.50 (s, 9H), 2.28 (d, J=I .2 Hz, 3H), 4.03 (s, 3H), 6.83 (brs, IH), 6.97-7.02 (m, 3H), 7.51 (d, J=8.0 Hz, IH), 7.59 (d, J=15.2 Hz, IH), 7.82 (s, IH), 8.01 (br s, IH). Example 8 [0072] Synthesis of (2EV3- [6-methoxy-5 -(4-methyl- 1 H-imidazol- 1 -vDpyridin-2- yl] acrylohydrazide [Formula 42]
Figure imgf000034_0002
[0073]
4 N hydrogen chloride-ethyl acetate (12.5 mL) was added to a suspension of the compound obtained in Example 7 (2.50 g) in chloroform (12.5 mL) under ice-cooling, followed by stirring at room temperature for 30 minutes. Then, chloroform (12.5 mL) was added, followed by stirring for 1.5 hours. Saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, methanol and chloroform were added and then the organic layer was separated.
The aqueous layer was extracted with chloroform. The organic layers were mixed and washed with saturated aqueous sodium chloride. The resulting organic layer was dried over MgSO4.
The salt was removed by filtration, and then the filtrate was concentrated to obtain 1.19 g of a solid. Methanol (7.5 mL) was added to 296 mg of the solid, followed by dissolution at 600C.
Then, the solution was cooled to room temperature. The solid was collected by filtration, washed with MTBE and dried to obtain the title compound (200 mg).
1H-NMR (600 MHz, CD3OD): δ 2.15 (d, J = 0.9 Hz, 3H), 3.98 (s, 3H), 7.00 (d, J = 15.3 Hz, IH),
7.09 (dd, J = 1.3, 0.9 Hz, IH), 7.10 (d, J = 7.8 Hz, IH), 7.40 (d, J = 15.2 Hz, IH), 7.68 (d, J = 7.6 Hz, IH), 7.85 (d, J = 1.3 Hz, IH)
Example 9
[0074]
(2E)-Nt-{(4SV4-Cvano-4-r2-(trifluoromethvnphenyl1butvU-3-r6-methoxy-5-(4-methyl-lH- imidazol- 1 -yl)pyridin-2-yl]acrylohvdrazide [Formula 43]
Figure imgf000035_0001
[0075]
The compound obtained in Example 8 (743.2 mg, 3.08 mmol) was weighed in a reaction vessel. Subsequently, the atmosphere in the reaction vessel was replaced by nitrogen gas. THF (16 mL) was added to the reaction vessel, followed by dissolution at room temperature. Then, the compound 18 (800.7 mg, 2.93 mmol) and tosyl acid monohydrate (167.2 mg, 0.879 mmol) were added, followed by stirring for 30 min. The reaction mixture was ice- cooled and then sodium triacetoxyborohydride (3105 mg, 14.65 mmol) was added. Thereafter, the mixture was heated to room temperature and stirred for two hours and 45 minutes. Ethyl acetate and 10% aqueous sodium bicarbonate were introduced into the reaction mixture, and then the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The resulting organic layer was concentrated and then purified by silica gel chromatography (eluent: ethyl acetate/methanol = 20/1 -> 15/1) to obtain the title compound (1.444 g, 2.90 mmol, yield:
99%, >98% ee).
1H-NMR (600 MHz, CDCl3): δ 7.84 (s, IH), 7.74-7.68 (m, 2H), 7.64 (t, J = 7.6 Hz, IH), 7.59 (d,
J = 14.9 Hz, IH), 7.54 (d, J = 7.6 Hz, IH), 7.49-7.43 (m, IH), 7.06 (d, J = 7.6 Hz, IH), 6.98 (s, IH), 6.92 (d, J = 14.9 Hz, IH), 4.27 (dd, J = 10.0, 5.2 Hz, IH), 4.06 (s, 3H), 2.99 (t, J = 6.72 Hz,
2H), 2.30 (s, 3H), 2.10-1.95 (m, 2H), 1.91-1.82 (m, IH), 1.80-1.70 (m, IH)
Example 10
[0076]
Synthesis of (8SV2-{(EV2-r6-methoxy-5-(4-methyl-lH-imidazol-l-vnpyridin-2-vnvinvU-8-r2- (trifluoromethyπphenyl]-5.6.7.8-tetrahvdro[l,2,41triazolofl,5-a]pyridine
[Formula 44]
Figure imgf000036_0001
[0077]
The compound obtained in Example 9 (95.8 mg, purity: 63.0 wt%, 0.121 mmol, >98% ee) was dissolved in toluene (1.92 ml) and acetic acid (0.38 ml) at room temperature in a nitrogen atmosphere. Then, the solution was heated to 700C and stirred for 13 hours. The reaction solution was air-cooled to room temperature. Thereafter, the reaction solution was quantitatively analyzed by the HPLC external standard method to determine the yield (yield: 63.9%). The optical purity was measured by chiral HPLC to be 39.3% ee. Example 11 [0078] Synthesis of 2-{(EV2-r6-methoxy-5-(4-methyl-lH-imidazol-l-vnpyridin-2-yl1vinvU-8-r2- (trifluoromethyl)phenyll-5.6.7,8-tetrahydro[ 1.2.4]triazolor 1 ,5-a]pyridine [Formula 45]
Figure imgf000037_0001
[0078] The compound obtained in Example 10 (56.9 mg, 0.114 mmol) was dissolved in toluene (1.14 ml) and acetic acid (0.23 ml) at room temperature in a nitrogen atmosphere. Then, the solution was heated to 800C and stirred for 23.5 hours. Thereafter, the reaction solution was air-cooled to room temperature and concentrated under reduced pressure to obtain the title compound. The resulting crude product was quantitatively analyzed by the HPLC external standard method to determine the yield (yield: 95.1 %).
IH-NMR (400 MHz; CDC13) δ (ppm): 1.91-2.01 (IH, m), 2.10-2.21 (IH, m), 2.23-2.28 (lH,m), 2.29 (3H, d, J=LO), 2.43-2.50 (IH, m), 4.03(3H, s), 4.29 4.40 (2H, m), 4.71 (IH, dd, J=6.0,8.4Hz), 6.93 (IH, d, J=7.8Hz), 6.95 (IH, dd, J=LOHz), 7.02 (IH, d, J=7.8Hz), 7.39 (IH, dd, J=7.6Hz), 7.43 (IH, d, J=15.6Hz), 7.46 (IH, d, J=7.8Hz), 7.49 (IH, dd, J=7.3Hz), 7.64 (IH, d, J=15.6Hz), 7.73 (IH, d, J=7.1Hz), 7.76 (IH, d, J=1.2Hz). Example 12 [0079]
Synthesis of (2E)-N'-(4-Cvano-4-r2-('trifluoromethvπphenvnbutvU-3-r6-methoxy-5-(4-methyl- 1 H-imidazol- 1 -vQpyridin-2- yll acrylohvdrazide [Formula 46]
Figure imgf000038_0001
[0080] Step l
2-(Trifluoromethyl)phenylacetonitrile (4.75 g, 25.63 mmol) was dissolved in THF (33 ml) at room temperature under nitrogen atmosphere, and then cooled to -8°C. Potassium tert-butoxide (2.75 g, 24.52 mmol) was slowly added and the mixture was stirred 30 minutes at 00C. The mixture was cooled to -5°C, bromopropionaldehyde dimethyl acetal (3.0 ml, 922.29 mmol) was added dropwise and stirred 16.5 hours at 00C. A saturated aqueous ammonium chloride solution (24 ml), water (2 ml) and MTBE (24 ml) were added to the reaction mixture, and the aqueous layer was separated. 5N hydrochloric acid (58 ml) was added to the organic layer, and then stirred 5 hours at room temperature. Organic layer was separated and the aqueous layer was extracted twice with MTBE (30 ml), and then the three organic layers were combined. The obtained aldehyde was used as MTBE solution. Step 2 The compound obtained in Example 7 (6.40 g, 17.15 mmol) was suspended in
THF (64 ml), and then cooled by ice-bath. Trimethylsilylmethyl trifluoromethansulfonate (4.65 ml, 25.73 mmol) was added dropwise, and then stirred for 15 minutes. Pyridine (4.16 ml, 51.45 mmol), the aldehyde solution obtained in step 1 and water (0.31 ml, 17.15 mmol) were added, and then stirred at room temperature for 10 minutes. The reaction mixture was cooled by ice- bath, and 2N sodium hydroxide solution (19.9 ml), water (20 ml) and EtOAc (30 ml) were added. The aqueous phase was separated. The organic phase was washed with saturated aqueous sodium chloride solution (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was suspended in EtOAc (30 ml), and the solids were collected by filtration, washed with EtOAc and dried to obtain the title compound (6.15 g, yield 72.3%). 1H NMR (400MHz, CDCl3) δ 1.17-2.02 (m, 4H), 3.32 (d, J = 0.7Hz, 3H), 3.33 (d, J = 0.7Hz, 3H), 4.25 (dd, J = 9.0, 5.6 Hz, IH), 4.40 (dd, J = 5.4, 4.6Hz, IH), 7.45 (dd, J = 7.3, 7.8Hz, IH), 7.63 (dd, J = 7.3, 7.6Hz, IH), 7.70 (dd, J = 7.6, 8.1Hz, IH). Example 13 [0081]
Synthesis of Ethyl (2S)-5-chloro-2-[2-(trifluoromethyl)phenyl1pentanimidoate hydrochloride [Formula 47]
Figure imgf000039_0001
[0082]
After the bubbling of HCl gas 10 minutes into the solution of Compound 16 (815 mg) in ethanol (12 ml) with ice-bath cooling, the mixture was stirred at room temperature for 7 hours. The mixture was concentrated under reduced pressure, and cyclopentylmethylether (4 ml) was added the residue to crystallize. The mixture was stirred at room temperature for 30 minutes, and then stirred 30 minutes with ice-bath cooling. The solids were collected by filtration, dried under reduced pressure to obtain the titled compound (765mg). ESI-MS;m/z 308 [M+-Cl].
1H NMR (400MHz, CDCl3): δ 1.40 (t, J = 7.2 Hz, 3H), 1.65 - 1.80 (m, IH), 1.83 - 1.96 (m, IH), 2.33 - 2.44 (m, IH), 2.52 - 2.62 (m, IH), 3.53 - 3.64 (m, 2H), 4.47 (t, J = 8.0 Hz, IH), 4.66 (q, J = 6.8 Hz, 2H), 7.48 (t, J = 7.6 Hz, IH), 7.67 (t, J = 7.6 Hz, IH), 7.72 (d, J = 7.6 Hz, IH), 7.86 (d, J = 7.6 Hz, IH), 12.06 (brs, IH), 12.52 (brs, IH). Example 14 [0083] Synthesis of (3SV2-Imino-3-[2-(trifluoromethvπphenyl]piperidin-l-amine hydrochloride [Formula 48]
Figure imgf000040_0001
[0084]
Saturated aqueous sodium hydrogen carbonate solution (3 ml) and ethanol (1 ml) were added to the suspension of the compound obtained in Example 13 (500 mg) in tert-butylmethylether (3 ml), and the mixture was stirred at room temperature for 10 minutes. Aqueous phase was separated, and the organic layer was washed with saturated aqueous sodium chloride solution, dried over potassium carbonate. The salt was removed by filtration, and the filtrate was concentrated under reduced pressure. The solution of hydrazine monohydrate (72 mg) in ethanol (0.5 ml) was added dropwise to the solution of the residue in ethanol (3 ml), and then the mixture was stirred at room temperature for 23 hours. The mixture was concentrated under reduced pressure, and crystallized in ethanol (0.4 ml) and heptane (0.6 ml) with sonication. Heptane (3 ml) was added to the mixture, the solids were collected by filtration and dried under reduced pressure to obtain the titled compound (342mg). ESI-MS;m/z 258 [M+-Cl].
1H NMR (400MHz, DMSO-D6): δ 1.67 - 2.00 (m, 3H), 2.05 - 2.15 (m, IH), 3.61 - 3.80 (m, 2H), 4.33 (t, J = 6.8 Hz, IH), 5.54 (s, 2H), 7.41 (d, J = 7.6 Hz, IH), 7.58 (t, J = 7.6 Hz, IH), 7.72 (t, J = 7.6 Hz, IH), 7.79 (d, J = 7.6 Hz, IH), 8.47 (brs, IH), 8.58 (brs, IH). Example 15 [0085]
Synthesis of Methyl (2EV3-f6-methoxy-5-(4-methyl-lH-imidazol-l-vπpyridin-2-yl]acrylate [Formula 49]
Figure imgf000040_0002
[0086]
Triethylamine (6.5 ml) was added to the suspension of compound 4 (5.0 g), tris (dibenzylydeneacetone) dipalladium (856 mg), Tri(o-tolyl)phosphine (569 mg), methylacrylate (3.4 ml) in DMF (35 ml), and the mixture was stirred at 1000C for 55 minutes. The mixture was cooled to room temperature, and then passed through celite. The filtrate was concentrated under reduced pressure, and ethyl acetate (100 ml) and water (100ml) were added to the residue. The precipitated solids were removed by filtration with celite, and saturated sodium hydrogen carbonate (10 ml) was added to the filtrate. The organic phase was dried over MgSO4, and the salt was removed by filtration, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/heptane), concentrated under reduced pressure. The residual solids were purified by reslurry in the mixture of ethyl acetate and heptane, collected by filtration and dried under reduced pressure to obtain the titled compound (3.58mg). ESI-MS;m/z 274 [M+-Cl].
1H NMR (400MHz, CDCl3): δ 2.30 (s, 3H), 3.84 (s, 3H), 6.96 (d, J = 15.6 Hz, IH), 6.99 (s, IH), 7.07 (d, J = 7.6 Hz, IH), 7.54 (d, J = 7.6 Hz, IH), 7.59 (d, J = 15.6 Hz, IH), 7.83 (s, IH). Example 16 [0087] Synthesis of (2E)-3-r6-Methoxy-5-(4-methyl- 1 H-imidazol- 1 -vQpyridin-2-vπ acrylic acid
Figure imgf000041_0001
[0088]
2N sodium hydroxide solution was added dropwise to the suspension of the compound obtained in Example 15 (2.5 g) in methanol (5 ml), and the mixture was stirred at room temperature for 65 minutes. THF (2.5 ml) was added and the mixture was stirred for 16.5 hours. The mixture was concentrated under reduced pressure, and pH of the residual aqueous phase was adjusted to 5 by 2N hydrochloric acid with ice-bath cooling. The mixture was stirred 40 minutes with ice-bath cooling, the precipitated solids were collected by filtration and dried under reduced pressure to obtain the titled compound (2.31 g). ESI-MS;m/z 260 [M+-Cl].
1H NMR (400MHz, DMSO-D6): δ 2.16 (s, 3H), 4.00 (s, 3H), 6.83 (d, J = 15.6 Hz, IH), 7.29 (s, IH), 7.43 (d, J = 7.6 Hz, IH), 7.58 (d, J = 15.6 Hz, IH), 7.90 (d, J = 15.6 Hz, IH), 7.96 (s, IH), 12.61 (brs, IH). Example 17
Synthesis of (8SV2-{(Ε)-2-r6-Methoxy-5-(4-methyl-lH-imidazol-l-vnpyridin-2-yllvinvU-8-r2- (trifluoromethvπphenyll-5,6J,8-tetrahvdrofl,2,41triazolofK5-a]pyridine [0089]
[Formula 51]
Figure imgf000042_0001
[0090]
Thionyl chloride (5IuL) was added to the suspension of compound obtained in Example 16 (200 mg) in DMF (2 ml), and the mixture was stirred at room temperature for 25 minutes. The compound obtained in Example 14 (113 mg) was added to the mixture, and the mixture was stirred at room temperature for 95 minutes. Triethylamine (0.33 ml) was added to the mixture, and the mixture was stirred at room temperature for 10 minutes and at 7O0C for 1 hour. Ethyl acetate, water and saturated sodium hydrogen carbonate solution were added to the mixture, and the organic layer was washed with saturated sodium chloride solution. The organic layer was dried over MgSO4 and the salt was removed by filtration. The solution was concentrated under reduced pressure, and the residue was purified by NH-silica gel chromatography (ethyl acetate/heptane) and concentrated under reduced pressure to obtain the titled compound (85.6mg, 27.4%ee). IH-NMR (400 MHz; CDC13) δ (ppm): 1.91-2.01 (IH, m), 2.10-2.21 (IH, m), 2.23-2.28 (lH,m), 2.29 (3H, d, J=LO), 2.43-2.50 (IH, m), 4.03(3H, s), 4.29 4.40 (2H, m), 4.71 (IH, dd,
J=6.0,8.4Hz), 6.93 (IH, d, J=7.8Hz), 6.95 (IH, dd, J=LOHz), 7.02 (IH, d, J=7.8Hz), 7.39 (IH, dd, J=7.6Hz), 7.43 (IH, d, J=15.6Hz), 7.46 (IH, d, J=7.8Hz), 7.49 (IH, dd, J=7.3Hz), 7.64 (IH, d, J=15.6Hz), 7.73 (IH, d, J=7.1Hz), 7.76 (IH, d, J=1.2Hz).
INDUSTRIAL APPLICABILITY [0091]
The present invention can efficiently produce a 2-vinyl-5,6,7,8- tetrahydro[l,2,4]triazolo[l,5-a]pyridine derivative that has not yet been described in any documents, in particular, (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2- yl]vinyl}-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[l,2,4]triazolo[l,5-a]pyridine.

Claims

1. A process for producing a compound represented by the formula (I):
[Formula 2]
Figure imgf000044_0001
wherein A represents an aryl group which may have 1 to 3 substituents selected from Substituent Group A or a heteroaryl group which may have 1 to 3 substituents selected from Substituent Group A; and B represents an aryl group which may have a substituent selected from Substituent Group B or a heteroaryl group which may have 1 to 3 substituents selected from Substituent Group A, or a salt thereof, the process comprising the step of: heating a compound represented by the formula (II): [Formula 1]
Figure imgf000044_0002
wherein A and B are as defined above, or a salt thereof in a solvent in the presence of an acid;
Substituent Group A: a halogen atom, a lower alkyl group having 1 to 6 carbon atoms which may have 1 to 3 substituents selected from Substituent Group Al, a lower alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 substituents selected from Substituent Group Al, an aryl group which may have 1 to 3 substituents selected from Substituent Group A2 and a heteroaryl group which may have 1 to 3 substituents selected from Substituent Group A2;
Substituent Group Al : a hydroxyl group, a halogen atom, a cyano group and a lower alkoxy group having 1 to 6 carbon atoms;
Substituent Group A2: a halogen atom and a lower alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms;
Substituent Group B: a halogen atom, a cyano group, a nitro group, a lower alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms and a lower alkoxy group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms.
2. The production process according to claim 1, wherein the process produces a compound represented by the formula (1-1) where A is the formula A2-A1-: [Formula 4]
Figure imgf000045_0001
wherein A1 represents an aryl group which may have 1 to 3 substituents selected from Substituent Group Al or a heteroaryl group which may have 1 to 3 substituents selected from Substituent Group Al ; A2 represents an aryl group which may have 1 to 3 substituents selected from Substituent Group A2 or a heteroaryl group which may have 1 to 3 substituents selected from Substituent Group A2; and B is as defined in claim 1, or a salt thereof using a compound represented by the formula (II- 1): [Formula 3]
Figure imgf000045_0002
wherein Ai, A2 and B are as defined above, or a salt thereof;
Substituent Group Al: a hydroxyl group, a halogen atom, a cyano group and a lower alkoxy group having 1 to 6 carbon atoms;
Substituent Group A2: a halogen atom and a lower alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms.
3. The production process according to claim 2, wherein A1 is a phenyl group which may have 1 to 3 substituents selected from Substituent Group Al or a pyridyl group which may have 1 to 3 substituents selected from Substituent Group Al.
4. The production process according to claim 2, wherein A2 is an imidazolyl group which may have 1 to 3 substituents selected from Substituent Group A2.
5. The production process according to any one of claims 1 to 4, wherein B is a phenyl group which may have a substituent selected from Substituent Group B.
6. A process for producing 2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l- yl)pyridin-2-yl]vinyl}-8-[2-(trifluoromethyl)phenyl]-5,6,758-tetrahydro[l,2,4]triazolo[l,5- a]pyridine represented by the formula (1-2): [Formula 6]
Figure imgf000046_0001
or a salt thereof, the process comprising the step of: heating (2E)-N'-{4-cyano-4-[2- (trifluoromethyl)phenyl]butyl}-3-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2- yljacrylohydrazide represented by the formula (II-2): [Formula 5]
Figure imgf000046_0002
or a salt thereof in a solvent in the presence of an acid.
7. A process for producing (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l- yl)pyridin-2-yl]vinyl}-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[l,2,4]triazolo[l,5- ajpyridine represented by the formula (1-3):
[Formula 10]
Figure imgf000046_0003
or a salt thereof, the process comprising the steps of: reacting (2S)-5-oxo-2-[2- (trifluoromethyl)phenyl]pentanenitrile represented by the formula (1): [Formula 7]
Figure imgf000047_0001
or a salt thereof with (2E)-3-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2- yljacrylohydrazide represented by the formula (2): [Formula 8]
Figure imgf000047_0002
or a salt thereof to convert the compound of the formula (1) or the salt thereof to (2E)-N1- { (4S)- 4-cyano-4-[2-(trifluoromethyl)phenyl]butyl}-3-[6-methoxy-5-(4-methyl-lH-imidazol-l- yl)pyridin-2-yl]acrylohydrazide represented by the formula (II-3): [Formula 9]
Figure imgf000047_0003
or a salt thereof; and heating the compound of the formula (II-3) or the salt thereof in a solvent in the presence of an acid.
8. (2E)-Nl-{(4S)-4-Cyano-4-[2-(trifluoromethyl)phenyl]butyl}-3-[6-methoxy-5-(4- methyl-lH-imidazol-l-yl)pyridin-2-yl]acrylohydrazide represented by the formula (II-3): [Formula 11]
Figure imgf000047_0004
( I 1 - 3 ) or a salt thereof.
9. A process for producing (2S)-5-oxo-2-[2-(trifluoromethyl)phenyl]pentanenitrile represented by the formula (1): [Formula 19]
Figure imgf000048_0001
or a salt thereof, the process comprising the steps of: reacting 2-trifluoromethylphenylacetic acid represented by the formula (3): [Formula 12]
Figure imgf000048_0002
or a salt thereof with (S)-(+)-4-phenyl-2-oxazolidinone represented by the formula (4): [Formula 13]
Figure imgf000048_0003
or a salt thereof to convert the compound of the formula (3) or the salt thereof to (4S)-4-phenyl- 3-{[2-(trifluoromethyl)phenyl]acetyl}-l,3-oxazolin-2-one represented by the formula (5): [Formula 14]
Figure imgf000048_0004
or a salt thereof; reacting the compound of the formula (5) or the salt thereof with l-chloro-3- iodopropane to convert the compound of the formula (5) or the salt thereof to (4S)-3-{(2S)-5- chloro-2-[2-(trifluoromethyl)phenyl]pentanoyl}-4-phenyl-l,3-oxazolin-2-one represented by the formula (6): [Formula 15]
Figure imgf000049_0001
or a salt thereof; hydrolyzing the compound of the formula (6) or the salt thereof to convert the compound of the formula (6) or the salt thereof to (2S)-5-chloro-2-[2- (trifluoromethyl)phenyl]pentanoic acid represented by the formula (7): [Formula 16]
Figure imgf000049_0002
or a salt thereof; converting the compound of the formula (7) or the salt thereof to (2S)-5-chloro-2- [2-(trifluoromethyl)phenyl]pentanoic acid amide represented by the formula (8): [Formula 17]
Figure imgf000049_0003
or a salt thereof; converting the compound of the formula (8) or the salt thereof to (2S)-5-chloro-2- [2-(trifluoromethyl)phenyl]pentanenitrile represented by the formula (9): [Formula 18]
Figure imgf000049_0004
( 9 ) or a salt thereof; and reacting the compound of the formula (9) or the salt thereof. 10. A compound represented by the following formula:
[Formula 20]
Figure imgf000050_0001
or a salt thereof.
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