WO2007058305A1 - シンナミド誘導体の製造方法 - Google Patents
シンナミド誘導体の製造方法 Download PDFInfo
- Publication number
- WO2007058305A1 WO2007058305A1 PCT/JP2006/322982 JP2006322982W WO2007058305A1 WO 2007058305 A1 WO2007058305 A1 WO 2007058305A1 JP 2006322982 W JP2006322982 W JP 2006322982W WO 2007058305 A1 WO2007058305 A1 WO 2007058305A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- chemical
- group
- compound
- same meaning
- Prior art date
Links
Classifications
-
- 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
- C07D401/10—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 linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
Definitions
- the present invention shows a cinamide derivative not described in any literature, particularly an amyloid ⁇ production-reducing action, and is useful as a progression inhibitor or preventive for amyloid ⁇ -related diseases such as Alzheimer's disease (3 ⁇ )- 1-[(1S) -1- (4-Fluorophenyl) ethyl] -3- [3-Methoxy-4— (4-Methyl-1 H-imidazole-1-yl) benzylidene] piperidine-2—
- the present invention relates to a method for producing ON and a synthetic intermediate thereof.
- Alzheimer's disease is a disease characterized by the formation of senile plaques and neurofibrillary tangles as well as degeneration and loss of nerve cells.
- treatment of Alzheimer's disease is limited to symptomatic treatment with symptom ameliorating agents represented by acetylcholine esterase inhibitors, and the fundamental therapeutic agents that suppress the progression of the disease have been developed.
- Development of a method for controlling the cause of the pathogenesis is necessary for the creation of a therapeutic agent for Alzheimer's disease.
- a / 3 protein which is a metabolite of amyloid precursor protein (hereinafter referred to as APP), is thought to be greatly involved in the degeneration and loss of neuronal cells and the development of dementia symptoms (for example, non-patent literature) 1 and 2). Therefore, compounds that reduce the production of A / 340 and 42 are expected as a progression inhibitor or preventive agent for Alzheimer's disease.
- Non-patent literature l Klein WL, 7 others, Alzheimer's disease— affected brain: Presence of oligomeric A ligands (ADDLs) suggests a molecular bas is for reversible memory loss, Proceding National Academy of Science USA 2003, Sep 2 ; 100 (18), p. 10417-10422.
- Non-Patent Document 2 Nitsch RM, 16 others, Antibodies against ⁇ -amyloid slow cognitive decline in Alzheimer's disease, Neuron, 2003, May 22; 3 8, p. 547-554.
- the object of the present invention is to provide a cinamide derivative, particularly (3 ⁇ ) -1-[(1S) -1- (4-fluorophenyl) ethyl] -3- [3-methoxy-4-one (4 It is an object of the present invention to provide a method for producing —methyl- 1H-imidazole-1-yl) benzylidene] piperidin 2-one and a method for producing a synthetic intermediate thereof.
- R may have a substituent, a C16 alkyl group or a substituent.
- R may have a C16 alkyl group which may have a substituent or a substituent
- R represents a 6- to 14-membered aromatic hydrocarbon ring group which may have a substituent or a 5- to 14-membered aromatic heterocyclic group which may have a substituent
- Q and n are A process for producing the compound (8) represented by the above definition and the same meaning; [2].
- R is the same as defined in [1] above.
- R X and n have the same meaning as defined in [1] above, and Q is defined in [7] above.
- L is an ester group or one CO—NR (—OR) (wherein R is C 1-6
- the step comprises removing the protecting group
- R represents a C1-6 alkyl group
- R represents a protecting group for a carboxynole group
- n is as defined in the above [1].
- R represents the same meaning as defined in [24] above).
- the structural formula of a compound may represent a certain isomer for convenience.
- all geometrical isomers generated in the structure of the compound optical isomers based on asymmetric carbons.
- crystal polymorphs may exist but are not limited to the same, and any single crystal form or a mixture thereof may be a solvate such as a hydrate other than an anhydride. Also good.
- the compound to be used and the objective compound to be produced may be either a salt or a salt.
- the salt include inorganic acid salts (for example, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, hydrofluoride, hydrochloride, hydrogen bromide).
- Acid salts hydroiodide salts, etc.
- organic carboxylates eg acetate, oxalate, maleate, tartrate, fumarate, kenate, etc.
- organic sulfonic acids Salt eg methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, etc.
- amino acid salt eg aspartate, glutamate, etc.
- Quaternary amine salts alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, magnesium salts, calcium salts, etc.), and the like.
- Disease associated with amyloid / 3 refers to various diseases such as Alzheimer's disease in which amyloid ⁇ is involved.
- an optionally substituted 6 to 14-membered aromatic hydrocarbon ring group and “an optionally substituted 5 to 14-membered aromatic heterocyclic group”
- the “6- to 14-membered aromatic hydrocarbon ring group” and the “5- to 14-membered aromatic heterocyclic group” have the following meanings.
- the "6- to 14-membered aromatic hydrocarbon ring group” refers to a monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring group having 6 to 14 carbon atoms, which is preferable in the group.
- the group may be monocyclic, bicyclic or tricyclic, such as phenenyl group, indenyl group, naphthyl group, azulenyl group, heptalenyl group, biphenyl group, fluorenyl group, phenalenyl group, phenanthrenyl group, anthracenyl group. 6- to 14-membered cyclic aromatic hydrocarbon ring group.
- the “5- to 14-membered aromatic heterocyclic group” refers to a monocyclic, bicyclic or tricyclic aromatic heterocyclic group having 5 to 14 carbon atoms, and preferred groups in the group include, for example, (1) Pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyraduryl group, virazolinyl group, imidazolinole group, indolinole group, isoindolyl group, indolizinyl group, purinyl group, indazolyl group, quinolyl group, isoquinolyl group, quinolidinyl group, phthaladilyl group Group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group, cinnolinino group, pteridinyl group, imidazotriazinyl group, birazinopyridazinyl group, attaridinyl
- substituted 6- to 14-membered aromatic hydrocarbon cyclic group and the “optionally substituted 5- to 14-membered aromatic heterocyclic group” It means 1 to 3 substituents selected from Substituent Group A1.
- Substituent group A1 consists of (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano group, (5) nitro group, (6) C3-8 cycloalkyl group, (7) C2— 6 Alkenino group, (8) C2-6 alkynyl group, (9) C3-8 cycloalkoxy group, (10) C3-8 cycloalkylthio group, (11) Monoreminore group, (12) G1-6 Norequinole Canoleboninole group, (13) G1-6 endolequinoleci group, (14) C1 6 alkylsulfinyl group, (15) C1-6 alkylsulfonyl group, (16) hydroxyimino group, (17) C1-6 alkoxy A mino group, (18) a C1 6 alkyl group optionally substituted with 1 or 3 substituents selected from substituent group A2, and (19) a 1 to 3 substituent selected from substituent group A2.
- An optionally substituted C16 alkoxy group (20) an amino group optionally substituted with one or two substituents selected from substituent group A2, (21) a substituent A rubamoyl group optionally substituted with 1 to 2 substituents selected from A2, (22) 1 selected from substituent group A 2 and 5 substituted with 5 substituents; 6-membered, 14-membered aromatic hydrocarbon ring group, (23) 5- to 14-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from Substituent Group A2 (24 ) Substituent substituted with 1 to 3 substituents selected from Substituent Group A2; 6-membered; 14-membered non-aromatic hydrocarbon ring group; (25) selected from Substituent Group A2 1 or 2 or 3 substituents, 5 or 14-membered non-aromatic heterocyclic group, (2 6) C2-6 alkenyloxy group, (27) C2-6 alkynyl An oxy group, (28) C3
- the substituent group A2 means (1) hydrogen atom, (2) halogen atom, (3) hydroxyl group, (4) cyano group, (5) nitro group, (6) C3_8 cycloalkyl group, (7 ) C2_6 alkenyl group, (8) C2-6-alkenoquinole group, (9) C3_8 cycloalkoxy group, (10) C3_8 cycloalkylthio group, (11) forminore group, (12) C1-6 alkylcarbonyl group (13) C1-6 alkylthio group, (14) C1-6 alkylsulfier group, (15) C1_6 alkylsulfonyl group, and (16) hydroxyimino group, (17) C1-6 alkoxyimino group Indicate
- the "substituent” in “having a substituent, C16 alkyl group” and “having a substituent, phenyl group” means a halogen atom, a hydroxyl group, a cyan group, And nitro group.
- Halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like, and preferably, for example, a fluorine atom, a chlorine atom, a bromine atom, and the like.
- C3-8 cycloalkyl group refers to a cyclic alkyl group having 3 to 8 carbon atoms, preferably, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a cycloheptyl group. Group, cyclooctyl group and the like.
- C2-6 alkenyl group refers to an alkenyl group having 2 to 6 carbon atoms, and is preferably a bur group, a aryl group, a 1 propenyl group, an isopropenyl group, a 1-butene 1 Linear or branched alkenyl groups such as 2-yl group, 1-butene-2-yl group, 1-butene-3-yl group, 2-butene-1-yl group, 2_butene_2-yl group, etc. Be mentioned
- C2_6 alkynyl group refers to an alkynyl group having 2 to 6 carbon atoms, preferably, for example, an ethur group, a 1_propynyl group, a 2_propynyl group, a butyr group, a pentyl group, Examples thereof include a linear or molecular chain alkynyl group such as a xishur group.
- C3_8 cycloalkoxy group refers to a group in which one hydrogen atom is substituted with an oxygen atom in a cyclic alkyl group having 3 to 8 carbon atoms, and is preferably a cyclopropoxy group, a cyclobutoxy group, for example. , Cyclopentoxy group, cyclohexoxy group, cycloheptyloxy group, cyclooctyloxy group and the like.
- C3_8 cycloalkylthio group refers to a group in which one hydrogen atom is substituted with a sulfur atom in a cyclic alkyl group having 3 to 8 carbon atoms. Examples include a pyrthio group, a cycloptylthio group, a cyclopentylthio group, a cyclohexylthio group, a cycloheptylthio group, and a cyclooctylthio group.
- C1_6 alkylcarbonyl group refers to a group in which one hydrogen atom is substituted with a carbonyl group in an alkyl group having 1 to 6 carbon atoms, and preferably includes, for example, an acetyl group, a propionyl group, and a petityl group. Groups and the like.
- C1_6 alkylthio group refers to a group in which one hydrogen atom is substituted with a sulfur atom in an alkyl group having 1 to 6 carbon atoms.
- a methylthio group, an ethylthio group, n examples thereof include propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, tert butylthio group, n pentylthio group, i pentylthio group, neopentylthio group, n-hexinoretio group, and 1 methylpropylthio group.
- C16 alkyl sulfinyl group refers to a group in which one hydrogen atom is substituted with a sulfinyl group on an alkyl group having 1 to 6 carbon atoms, and is preferably a methan sulfinyl group, Examples include ethanesulfiel group.
- C1 6 alkylsulfonyl group refers to a group in which one hydrogen atom is substituted with a sulfonyl group in an alkyl group having 1 to 6 carbon atoms.
- a methanesulfonyl group, an ethanesulfonyl group, etc. Is mentioned.
- C1-6 alkoxyimino group refers to a group in which a hydrogen atom of an imino group is substituted with a C1-6 alkoxy group, and preferred examples include a methoxyimino group and an ethoxyimino group.
- C1_6 alkyl group refers to an alkyl group having 1 to 6 carbon atoms, preferably, for example, methyl group, ethyl group, n_propyl group, i_propyl group, n_butyl group, i-butynole group, tert-butyl group, n-pentyl group, i-pentyl group, neopentyl group, n-hexyl group, 1_methylpropyl group, 1,2-dimethylpropyl group, 1_ethylpropyl group, 1_methyl_2_ethylpropyl group, 1_ethyl_2_methylpropyl group, 1,1,2-trimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group, 2 , 2-dimethylbutyl group, 2-ethylbutyl group, 1,3-dimethylbutyl group, 2-
- C 1_6 alkoxy group refers to a group in which a hydrogen atom of an alkyl group having 1 to 6 carbon atoms is substituted with an oxygen atom, preferably, for example, a methoxy group, an ethoxy group, n —Propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, sec butoxy group, tert-butoxy group, n-pentoxy group, i-pentoxy group, sec pentoxy group, tert pentoxy group, n— Hexoxy group, i-Hexoxy group, 1,2-Dimethylpropoxy group, 2-Ethynole propoxy group, 1_Methyl_2_Ethylpropoxy group, 1_Ethyl_2_Methylpropoxy group, 1, 1, 2 _Trimethylpropoxy group, 1,1-dimethylbutoxy group, 2,2_dimethylbutoxy group, 2-ethylbutoxy group, 1,
- amino group optionally substituted with a C16 alkyl group refers to an amino group that may be substituted with an alkyl group having 1 to 6 carbon atoms, preferably, for example, an amino group or a methylamino group. , An ethylamino group, a propylamino group, a dimethylamino group, and the like.
- the "6- to 14-membered non-aromatic hydrocarbon ring group” refers to a 6- to 14-cyclic aliphatic hydrocarbon group, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group.
- a cyclic aliphatic hydrocarbon group consisting of 6 to 14 carbon atoms, such as a naphthyl group, 6, 7, 8, 9-tetrahydro-5H-benzocycloheptyl group, 1,4-dihydronaphthalenyl group, etc. means.
- the "5- to 14-membered non-aromatic heterocyclic group” is 1) the number of atoms constituting the ring or 14; and 2) 1 to 5, for example, nitrogen in the atoms constituting the ring.
- Atoms, heteroatoms such as _ ⁇ _ or —S —, and 3) the ring may contain one or more carbonyl groups, double bonds or triple bonds 5 to 14 It represents not only a member non-aromatic heterocyclic monocyclic group but also a saturated heterocyclic group condensed with an aromatic hydrocarbon cyclic group, or a saturated hydrocarbon cyclic group or saturated heterocyclic group condensed with an aromatic heterocyclic group.
- the 5- to 14-membered non-aromatic heterocyclic group include, for example, azetidyl group, pyrrolidinyl group, piperidinyl group, azepa-binole group, azocanyl group, tetrahydrofuranyl group, tetrahydrobiranyl group, morpholinyl group, thiomorpholinyl group, Piperazinyl group, thiazolidinyl group, dioxanyl group, imida Zolinyl group, thiazolinyl group, 1,2_benzopyranyl group, isochromanyl group, chromabinol group, indolinyl group, isoindolinyl group, azaindanyl group, azatetrahydronaphthyl group, azachromanyl group, tetrahydrobenzofuranyl group, tetrahydrobenzozoenyl group,
- C2-6 alkenyloxy group refers to a group in which one hydrogen atom is substituted with an oxygen atom in an alkenyl group having 2 to 6 carbon atoms, preferably, for example, a vinyloxy group, Such as aryloxy group, 1-propenyloxy group, isopropenyloxy group, 1-butene 1-loxy group, 1-butene 2-yloxy group, 1-butene 3-yloxy group, 2-butene 1-yloxy group, 2-butene-2-yloxy group, etc.
- a linear or branched alkenyloxy group may be mentioned.
- C2_6 alkynyloxy group refers to a group in which one hydrogen atom is substituted with an oxygen atom in an alkynyl group having 2 to 6 carbon atoms, preferably an ethuroxy group, 1-propynyloxy group Group, 2_propynyloxy group, butyroxy group, linear or branched alkynyloxy group such as pentynyloxy group and hexyloxy group.
- C3_8 cycloalkyl sulfiel group refers to a group substituted with one hydrogen atom carbiel group in a cyclic alkyl group having 3 to 8 carbon atoms, preferably, for example, a cycloalkyl group.
- Examples thereof include a propyl sulfiel group, a cyclobutyl sulfiel group, a cyclopentyl sulfinino group, a cyclohexyl sulfinyl group, a cycloheptyl sulfiel group, and a cyclo octyl sulfinyl group.
- C3-8 cycloalkylsulfonyl group is a cyclic alkyl group having 3 to 8 carbon atoms.
- a group substituted by one hydrogen atom carbonyl group preferably, for example, a cyclopropinolesnorephoninore group, a cyclobutinoresnorephoninore group, a cyclopentinoresnorenoninore group, Examples thereof include a cyclohexylsulfonyl group, a cycloheptylsulfonyl group, a cyclooctylsulfonyl group, and the like.
- Substituent the substituent may have a protecting group
- 6-membered, 14-membered aromatic hydrocarbon ring group or substituent the substituent Examples of the protecting group in the 14-membered aromatic heterocyclic group include “Protective Groups In Organic Synthesis Second Edition”. By TW Greene and PGM Wuts John Wiley & Sons, Inc. "means a protecting group, but is not limited thereto.
- the hydroxyl protecting group includes a methoxymethyl group, a methylthiomethyl group, a tetrahydrofuranyl group, a 1 ethoxyethyl group, a tertbutyldimethylsilyl group, a benzyl group, a tert butyl group, an aryl group, a triphenylmethyl group, and the like. Is mentioned.
- the protecting group for carboxyl group includes methinole group, ethyl group, benzyl group, 2, 2, 2-trichlorodiethyl group, o nitrobenzole group, p nitrobenzyl group, p nitrobenzyl group, ⁇ ⁇ Toluenesulfonylethyl group, ⁇ methoxybenzyl group and the like can be mentioned.
- protecting groups for amino groups include ⁇ -formyl group, ⁇ -acetyl group, ⁇ -chloroacetyl group, ⁇ -benzoyl group, tert butyl group, N-phthalimide group, diphenylmethyl group, benzinole group, etc. Can be mentioned.
- Ester group refers to a C1-6 alkoxycarbonyl group, and includes a methoxycarbonyl group, an ethoxycanoleboninole group, an n-propoxycanenoboninole group, an i-propoxycanonoboninole group, and n-butoxy Carbonyl group, i_butoxycarbonyl group, sec butoxycarbonyl group, te rt_butoxycarbonyl group, n_pentoxycarbonyl group, i_pentoxycarbonyl group, sec pentoxycanoleponore group, tert pentoxycanoleboninore Group, n_hexoxycarbonyl group, i-hexoxycarbonyl group, 1,2-dimethylpropoxycarbonyl group, 2_ethylpropoxycarbonyl group, 1-methyl_2_ethylpropoxycarbonyl group, 1-ethyl-2- Methylpropoxycarbonyl group, 1,1,
- Carbonyl such as methylpentoxycarbonyl group, 3_methylpentoxycarbonyl group, hexyloxy group and the like.
- Halogen reagent refers to, for example, chlorine, bromine, iodine, NCS (N-chlorosuccinimide)
- NBS N-bromosuccinimide
- sulfuryl chloride thionyl chloride
- sulfuryl bromide sulfuryl bromide
- thionyl bromide sulfuryl bromide
- the "leaving group introduction reagent” includes, for example, a halogenating reagent, a sulfonylating reagent, an acylating reagent and the like.
- Sulfonylation reagent refers to a reagent that converts a hydroxyl group into a sulfonyloxy group.
- methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl, anhydrous methanesulfonic acid, anhydrous ⁇ toluene examples include sulfonic acid and trifluoromethanesulfonic anhydride.
- acylating reagent refers to a reagent for converting a hydroxyl group to an acyloxy group, and examples thereof include acetyl chloride, acetyl chloride and acetic anhydride.
- the "protecting group" of the hydrolyzable carboxynole group is preferably, for example, an ethyl ester group, a methyl ester group, ⁇ , ⁇ , ⁇ trichlorodiethyl ester group, ⁇ - ⁇ -toluene sulfonylethyl ester group, Examples include benzyl ester group, ⁇ -methoxybenzyl ester group, and ⁇ nitrobenzyl ester group.
- production methods of the present invention can be roughly classified into production methods 1, 2, 3 and 4 shown below.
- the production method comprises reacting compound (1) with compound (2) in the presence of a base,
- Step 1 — 1) can be performed by a commonly used method described in, for example, New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds [II] (page 1134, force is also page 1220). More specifically, this step can be performed with reference to the reaction conditions, post-reaction operations, purification methods and the like described in Example 5 described later.
- the compound represented by the formula (1) is a known compound, a commercially available compound, or a compound that can be easily produced from a commercially available compound by a method that is usually performed by those skilled in the art. Can do.
- the compound represented by the formula (2) a known compound, a commercially available compound, or a compound that can be easily produced from a commercially available compound by a method commonly used by those skilled in the art can be used.
- the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not hinder the reaction.
- the amount of compound (2) used can be increased or decreased as appropriate, but it is preferable that the amount of compound (1) can be used, for example, in an amount of 1 to 3 moles. For example, an amount of 1.0 force 1.3 times the mole can be used.
- the base used in this reaction is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, hydrogen carbonate, for example.
- Sodium, potassium hydrogen carbonate and the like can be mentioned, and more preferred are bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.
- the amount of the base used can be appropriately increased or decreased.
- the amount of the base is preferably about 50.0 times the amount of the compound (1). Also, it is the amount of monolith from ⁇ row exemption.
- the phase transfer catalyst used in this reaction is preferably, for example, benzyltrietyl ammonium chloride, benzyltriethyl ammonium bromide, tetra ⁇ -butyl ammonium fluoride, tetra ⁇ -butyl ammonium chloride, Tetra ⁇ -butyl ammonium bromide, more preferably, for example, benzyltriethyl ammonium chloride.
- the amount of the phase transfer catalyst used can be appropriately increased or decreased, but is preferably 0.05 to 5 times the amount of monolayer, more preferably to the compound (1). Is the amount of 0.15 times the amount of 0.05.
- the reaction temperature usually varies depending on the starting material, solvent, and other reagents used in the reaction, and can be appropriately changed.
- the reaction temperature is preferably 5 ° C to 50 ° C, and more preferably For example, 0 ° C to 30 ° C.
- the reaction time can be appropriately increased or decreased depending on the starting materials, the solvent, other reagents used in the reaction, the reaction temperature, and the degree of progress of the reaction.
- At the above reaction temperature preferably, for example, from 0.5 It is about 200 hours, more preferably about 96 hours, for example.
- the solvent used in the reaction for obtaining the ring-opened amide is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. , Toluene, xylene, isopropanol, tetrahydrofuran, tert-butyl methyl ether, cyclopentyl methyl ether, acetonitrile, N, N-dimethylformamide, 1,4-dioxane, 1,2-dimethoxyethane, 1-methyl-1-pyrrolidone , 1,3-dimethyl_2_imidazolidinone and a mixed solvent of water, more preferably, for example, a solvent such as toluene, cyclopentinoremethinoatenore, tert butinoremethinoreethenore It is a mixed solvent with water.
- the amount of compound (2) to be used can be appropriately increased or decreased, but it is preferable that the amount of compound (1) used is, for example, 1 to 3 times the molar amount. For example, an amount of 1.0 force 1.3 times the mole can be used.
- the base used in the reaction to obtain the ring-opened amide is preferably, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, Examples thereof include potassium hydrogen carbonate, and more preferable examples include bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.
- the amount of the base used in the reaction for obtaining the ring-opened amide can be appropriately increased or decreased, but is preferably 1.0 to 10.0 times the amount of the compound (1), for example, More preferably, it is an amount of 3.0 times mole, for example, 1 ⁇ 0 force.
- the reaction temperature of the reaction for obtaining the ring-opened amide is usually different depending on the starting materials, the solvent, and other reagents used in the reaction, and can be appropriately changed.
- the reaction time of the reaction for obtaining the ring-opened amide can usually be appropriately increased or decreased depending on the starting materials, the solvent, other reagents used in the reaction, the reaction temperature, and the progress of the reaction, but at the above reaction temperature. For example, it is preferably 0.5 to 200 hours, and more preferably 1 to 2 hours, for example.
- the solvent used in the reaction for cyclizing the ring-opened amide to obtain the compound represented by the formula (3) is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
- the base used in the reaction for cyclizing the ring-opened amide to obtain the compound represented by the formula (3) is preferably, for example, sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium. tert-butoxide, triethylamine, pyridine, diisopropylethylamine, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, carbonated potassium, cesium carbonate, sodium bicarbonate, potassium bicarbonate, etc. More preferred are bases such as sodium ethoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide and the like.
- the amount of the base used in the reaction for cyclizing the ring-opened amide to obtain the compound represented by the formula (3) can be appropriately increased or decreased, but preferably with respect to the compound (1), For example, 1.0 to 10.0 times the amount of monolith, and more preferably ⁇ , ⁇ to ⁇ or 1.0 power and 3.0 times the amount of monole.
- the reaction temperature of the reaction for cyclizing the ring-opened amide to obtain the compound represented by formula (3) usually varies depending on the starting material, the solvent, and other reagents used in the reaction, and can be appropriately changed. However, it is preferably, for example, 5 ° C to 50 ° C, and more preferably, for example, 0 ° C to 30 ° C.
- the reaction time for the reaction to cyclize the ring-opened amide to obtain the compound represented by the formula (3) is usually more appropriate depending on the starting material, the solvent, other reagents used in the reaction, the reaction temperature, and the progress of the reaction. Although it can be increased or decreased, it is preferably, for example, about 0.5 to 10 hours, more preferably about 0.5 to 1 hour at the above reaction temperature.
- the compound (15) represented by the formula (15) is a novel compound.
- the production method is a step of treating the compound (3) with a base and then converting it to a compound represented by the formula (4) by reacting with a halogenating reagent (hereinafter referred to as 1 — 2a). .
- l_2a can be performed by the method described in New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds [1] (pages 307 to 450). More specifically, this step can be performed with reference to the reaction conditions, post-reaction operations, purification methods and the like described in Example 6 described later.
- the compound (3) a compound or the like that can be produced by the method described in Example 3 and the like described later can be used.
- This reaction is preferably performed in a stream or atmosphere of an inert gas such as nitrogen or argon.
- the compound represented by the formula (3) can be produced by a person skilled in the art from a compound that can be produced by a method described in Example 5 and the like, a known compound, a commercially available compound, or a commercially available compound. A compound that can be easily produced by an ordinary method can be used.
- the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not hinder the reaction.
- tetrahydrofuran, 1, 2 Use dimethoxyethane, tert-butyl methyl ether, cyclopentyl methyl ether, jetyl ether, diisopropyl ether, dibutyl ether, dicyclopentyl ether, benzene, toluene, heptane, hexane, cyclohexane, or a mixed solvent thereof. More preferred is, for example, tetrahydrofuran, toluene, hexane, cyclohexane, or a mixed solvent thereof.
- n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide or the like can be used, and more preferably, for example, sec-butyllithium or tert-butyllithium and the like.
- the amount of the base to be used can be appropriately increased or decreased, but is preferably, for example, 1.0 power and 3.0 times the amount of the compound (3), more preferably, 1.1. Strength 1. It is 4 times the amount of mole.
- the temperature at which the base is reacted usually varies depending on the starting material, the solvent, and other reagents used in the reaction, and can be appropriately changed.
- the temperature is preferably from 78 ° C to 10 ° C. More preferably, for example, -78 ° C to _50 ° C.
- the reaction time of the base usually varies depending on the starting material, solvent, other reagents used in the reaction, reaction temperature, and the degree of progress of the reaction, and can be increased or decreased as appropriate. Preferably, for example, 10 minutes to 2 hours, more preferably about 2 About 0 minutes.
- the halogenating reagent used in this reaction is preferably, for example, chlorine, bromine or iodine.
- the amount of the halogen reagent used can be increased or decreased as appropriate, but is preferably, for example, 1 to 3 times the amount of compound (3), more preferably, for example, 1.05 to 1. The amount is twice as much.
- the temperature at which the halogenating reagent is reacted usually varies depending on the starting material, solvent, and other reagents used in the reaction, and can be changed as appropriate S, preferably from 78 ° C to -20 ° C, for example. More preferably, for example, 78 ° C. force to 40 ° C.
- the reaction time of the Rogeny reagent is usually dependent on the starting material, solvent, other reagents used in the reaction, reaction temperature, and the degree of progress of the reaction, and can be increased or decreased as appropriate.
- the reaction temperature is preferably, for example, 10 minutes to 2 hours, more preferably 20 minutes to 1 hour, for example.
- the production method is referred to as a step (hereinafter referred to as 12b) step of converting the compound represented by the formula (4) by reacting the compound (3) with a halogenating reagent in the presence of a base. ).
- Step 1-2b) can be carried out by the method described in J. of Organic Chemistry., (58), 3384-3386 (1993) A. O. King et al., Etc. More specifically, this step can be performed with reference to the reaction conditions, post-reaction operations, purification methods and the like described in Example 8 described later.
- Example 3 a compound or the like that can be produced by the method described in Example 3 and the like described later can be used.
- This reaction is preferably performed in a stream or atmosphere of an inert gas such as nitrogen or argon.
- the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not hinder the reaction.
- tetrahydrofuran, 1, 2— Dimethoxyethane, tert butyl methyl ether, cyclopentyl methyl ether, jetyl ether, diisopropyl ether, dibutyl ether, dicyclopentyl Ether, benzene, toluene, heptane, hexane, acetonitrile, methylene chloride, or a mixed solvent thereof can be used, and more preferably, for example, acetonitrile, salt methylene, tolylene, hexane, or cyclohexane. .
- the base used in this reaction is preferably, for example, triethylamine or jetylmethylamine.
- the amount of the base used can be increased or decreased as appropriate. However, it is preferable that the amount of the base (2.0) is preferably about 1.0 times the amount of monolith, more preferably about 0.75. , ⁇ ⁇ ⁇ 0 3. 0 force etc. 5 times the amount of mono.
- the halogenating reagent used in this reaction is preferably, for example, iodine trimethylsilane monoiodine, salt or trimethylsilane monoiodine.
- the amount of salt and trimethylsilane used can be increased or decreased as appropriate, but is preferably ⁇ or ⁇ or ⁇ or ⁇ or ⁇ . More preferably ⁇ , arrange ⁇ ⁇ .0 force 5
- the amount is 0 times mole.
- the amount of iodine or chlorine used can be increased or decreased as appropriate.
- the amount of the compound (3) is preferably ⁇ , ⁇ ⁇ . Also, ⁇ 5 5. 5 force, etc.
- the amount is 3.0 times mole.
- the reaction temperature usually varies depending on the starting material, solvent, and other reagents used in the reaction, and can be appropriately changed.
- the reaction temperature is preferably from 78 ° C to 20 ° C, more preferably, for example, -40 ° C to 10 ° C.
- the reaction time usually varies depending on the starting material, solvent, other reagents used in the reaction, reaction temperature, and the degree of progress of the reaction, and can be appropriately increased or decreased.
- the reaction temperature is preferably 30 minutes, for example. To 3 hours, more preferably about 1 hour, for example.
- the compound (16) represented by the formula (16) is a novel compound.
- the production method comprises a step of converting to a compound represented by the formula (6-a) by reacting a compound represented by the formula (4) with a phosphorous acid compound represented by the formula (5_a) (hereinafter referred to as “a”). 1 3) That's right. ).
- the phosphorous acid compound represented by the formula (5-a) is a known compound such as trimethyl phosphite, triethyl phosphite, triphenyl phosphite, 2, 2, 2-trifluoroethoxy phosphite, etc.
- a commercially available compound, or a compound that can be easily produced from a commercially available compound by a method commonly used by those skilled in the art can be used.
- the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not hinder the reaction.
- the amount of the compound represented by the formula (5-a) can be appropriately increased or decreased, but is preferably 1 to 15 times the amount of the compound (4), more preferably For example, the amount is 1.0 to 4.0 moles.
- the reaction temperature usually varies depending on the starting materials, the solvent, and other reagents used in the reaction, and can be appropriately changed.
- the reaction temperature is preferably 50 ° C to 150 ° C, and more preferably, For example 60.
- C power is also 100. C.
- the reaction time usually varies depending on the starting material, solvent, other reagents used in the reaction, the reaction temperature and the degree of progress of the reaction, and can be appropriately increased or decreased. Preferably, it is, for example, 1 to 20 hours, and more preferably, for example, 5 to 10 hours.
- the production method comprises a step of converting a compound represented by the formula (4) and a phosphorus compound represented by the formula (5_b) into a compound represented by the formula (6_b) ( Hereinafter referred to as 1_4) process. ).
- the phosphorus compound represented by the formula (5-b) is a known compound, for example, a commercially available compound such as triphenylphosphine or tri-n-butylphosphine, or a method usually carried out by those skilled in the art from a commercially available compound. Thus, a compound that can be easily produced can be used.
- the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not hinder the reaction.
- benzene, toluene, xylene, N, N-dimethylformamide, N-methylpyrrolidone, acetonitrile, dimethyl sulfoxide, tetrahydrofuran, jetyl ether, methanol, ethanol and the like or solvent-free is more preferable, for example, tetrahydrofuran.
- the amount of compound (5_b) used can be appropriately increased or decreased, but is preferably, for example, 1 to 15-fold mol, more preferably, for example, 1. relative to compound (4).
- the amount of force is 4.0 times mole.
- the reaction temperature usually varies depending on the starting material, solvent, and other reagents used in the reaction, and can be appropriately changed.
- the reaction temperature is preferably 50 ° C to 150 ° C, and more preferably For example 60.
- C power is also 100. C.
- the reaction time is usually determined by starting materials, solvents, other reagents used in the reaction, reaction temperature and Although it varies depending on the degree of progress of the reaction and can be appropriately increased or decreased, it is preferably, for example, 1 to 20 hours, more preferably 2 to 10 hours, for example, at the reaction temperature after adding the base.
- the production method comprises a step of converting to a compound (8) by reacting a compound represented by the formula (6-a) with a compound represented by the formula (7) in the presence of a base (hereinafter referred to as 1). 1) The process. ).
- the compound represented by the formula (6-a) is a compound that can be produced by a method described in Examples 7 and 9 described later, a known compound, a commercially available compound, or a commercially available compound. A compound that can be easily produced from such a compound by a method commonly used by those skilled in the art can be used.
- the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not hinder the reaction, but preferably, for example, 1,4-dioxane, Tetrahydrofuran, 1,2-Dimethoxyethane, tert-Butinoremethinoleethenore, Cyclopentinolemethinoleethenore, Getinoreethenore, Diisopropinoreethenore, Dibutinoreethenore, Dicyclopentylether, N, N— Dimethylformamide, N-methylpyrrolidone, cetonitrile, dimethylsulfoxide, methanol, ethanol, propanol, butanol or a mixed solvent thereof can be used, more preferably, for example, a mixed solvent of tetrahydrofuran and ethanol. be able to.
- the amount of compound (6-a) used can be increased or decreased as appropriate, but is preferably higher than that of compound (7). Amount, more preferably ⁇ , ⁇ ⁇ .
- the base used in this reaction is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or the like. More preferably, for example, sodium hydroxide, lithium hydroxide and the like.
- the amount of the base used can be appropriately increased or decreased.
- the base is preferably used in an amount of, for example, 1.0 to 5.0 moles, more preferably, relative to the compound (6_a). For example, 1.5 to 2.5 times the molar amount.
- the reaction temperature usually varies depending on the starting materials, the solvent, and other reagents used in the reaction, and can be appropriately changed.
- the reaction temperature is preferably 10 ° C to 50 ° C, and more preferably 15 °, for example. C to 30 ° C.
- the reaction time usually varies depending on the starting material, solvent, other reagents used in the reaction, reaction temperature, and the degree of progress of the reaction, and after adding a base that can be appropriately increased or decreased, at the above reaction temperature, Preferably it is for example 6 to 24 hours, more preferably for example about 18 hours.
- the compound obtained by force is the compound (3) which is the starting material and R has a protecting group
- the usual reaction for removing the protecting group can be used.
- a removal reaction a deprotection reaction described in many known literatures can be used (see, for example, TW Green. “Protective Groups in Organic Synthesis J, John Wiley & Sons. Inc., 1981). .
- the production method comprises a step of converting to a compound (8) by reacting a compound represented by formula (6-b) with a compound represented by formula (7) in the presence of a base (hereinafter referred to as 1). 1) The process. ).
- the compound represented by the formula (6-b) is a compound that can be produced by a method described in Example 17, etc. described below, a known compound, a commercially available compound, or a commercially available compound. Thus, a compound that can be easily produced by a method commonly used by those skilled in the art can be used.
- the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not hinder the reaction, but preferably, for example, 1,4 dioxane, tetrahydrofuran. 1,2-dimethoxyethane, tert butyl methyl ether, cyclopentyl methyl ether, jetyl ether, diisopropyl ether, dibutyl ether, dicyclopentyl ether, N, N dimethylformamide, N methyl pyrrolidone, acetonitrile, dimethyl sulfoxide, Methanol, ethanol, propanol, butanol or a mixed solvent thereof can be used, and more preferably, a solvent such as ethanol can be used.
- the amount of compound (6-b) used can be increased or decreased as appropriate, but is preferably higher than that of compound (7).
- the amount is more preferably ⁇ , ⁇ ⁇ . 0 force etc. 2.
- the amount is 0 times.
- the base used in this reaction is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, hydrogenated, for example.
- Sodium, sodium ethoxide, sodium methoxide, potassium t-butoxide, sodium t-butoxide, n-butyllithium and the like can be used. More preferred is, for example, triethylamine.
- the amount of the base used can be appropriately increased or decreased, but the base is preferably used in an amount of, for example, 1.0 to 5.0 moles, more preferably, 2 with respect to compound (6_b). 0 to 4.0 times the amount of moles.
- the reaction temperature usually varies depending on the starting materials, the solvent, and other reagents used in the reaction, and can be appropriately changed.
- the reaction temperature is preferably 10 ° C to 100 ° C, more preferably 40 °, for example.
- C force is 80 ° C.
- the reaction time usually varies depending on the starting material, solvent, other reagents used in the reaction, reaction temperature, and the degree of progress of the reaction, and can be appropriately increased or decreased. Preferably it is for example 6 to 24 hours, more preferably for example about 18 hours.
- the production method comprises a step of converting a compound represented by formula (3) into a compound represented by formula (9) by reacting the compound represented by formula (7) in the presence of a base (hereinafter referred to as “the compound represented by formula (9)”).
- 2-7) Process. a step of converting a compound represented by formula (3) into a compound represented by formula (9) by reacting the compound represented by formula (7) in the presence of a base (hereinafter referred to as “the compound represented by formula (9)”).
- Steps can be performed by commonly used methods such as those described in New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds [1] (51 page 1 to page 534). . More specifically, this step can be performed with reference to reaction conditions, post-reaction operations, purification methods and the like described in Example 1 and Example 22 described later.
- reaction in this step can also be performed under an air stream of an inert gas such as nitrogen or argon (or under an atmosphere of nitrogen or argon, for example).
- an inert gas such as nitrogen or argon (or under an atmosphere of nitrogen or argon, for example).
- the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not hinder the reaction, but preferably, for example, 1,4-dioxane, Tetrahydrofuran, 1,2-dimethoxyethane, tert-butenolemethinoleethenole, cyclopentinolemethinoleethenore, jetinoleethenore, diisopropinoleethenore, dibutinoleethenore, dicyclopentylether, benzene, toluene, Xylene, n-hexane, c-hexane, or a mixed solvent thereof can be used, and a mixed solvent of, for example, tetrahydrofuran and toluene is more preferable.
- the base is preferably a lithium amide such as n_butyllithium, sec_butyllithium, tert_butyllithium or lithium diisopropylamide, 2, 2, 6, 6-tetramethylpiperidine lithium amide, more preferably For example, lithium diisopropylamide Etc.
- a lithium amide such as n_butyllithium, sec_butyllithium, tert_butyllithium or lithium diisopropylamide, 2, 2, 6, 6-tetramethylpiperidine lithium amide, more preferably For example, lithium diisopropylamide Etc.
- the amount of compound (7) used can be increased or decreased as appropriate. However, it is preferable that the amount of compound (3) is 0.9. Preferably, the amount is 0.9 force and 1.5 times monore.
- compound (3) is treated with a base and then compound (7) is reacted in the next step.
- the reaction temperature between the compound (3) and the base usually depends on the starting material, solvent, and other reagents used in the reaction, and can be changed as appropriate. S, preferably, for example, 100 ° C to 0 ° C More preferably, it is, for example, 80 ° C to 0 ° C.
- the reaction time between the compound (3) and the base usually varies depending on the starting material, solvent, other reagents used in the reaction, reaction temperature and reaction rate, and can be increased or decreased as appropriate.
- the reaction temperature is preferably 10 minutes to 3 hours, and more preferably 30 minutes to 1 hour, for example.
- the reaction temperature between the base-treated compound represented by formula (3) and the compound represented by formula (7) usually varies depending on the starting material, solvent, and other reagents used in the reaction, and is appropriately set.
- Force that can be changed S Force that can be changed Preferably, for example, 100 ° C to 0 ° C, more preferably, for example, 80
- the reaction time between the base-treated compound represented by formula (3) and the compound represented by formula (7) usually depends on the starting material, solvent, other reagents used in the reaction, and the reaction temperature.
- the setting can be changed as appropriate, but after the base is added, the reaction temperature is preferably, for example, 10 minutes to 5 hours, more preferably, for example, 20 minutes to 2 hours.
- the step of converting compound (9) into compound (10-a) is the step 2-8a), and X is sulfoninole.
- the step of converting the compound (9) into the compound (10_a) is a step 2_8b), and in the case of an X force asinoleoxy group, the compound (9) is converted into the compound (10_b).
- Steps 2-8a), 2-8b) and 2-8c) were described in New Experimental Chemistry Course 14, Synthesis and Reaction of Organic Compounds [1] (pages 307 to 450), etc.
- Commonly used methods new experimental chemistry course 14 Synthesis and reaction of organic compounds [III] (pages 1793 to 1798) or new experimental chemistry course 14 Synthesis and reaction of organic compounds [II] (page 1000 To page 1062), etc., can be used. More specifically, this step can be performed with reference to the reaction conditions, post-reaction operations, purification methods and the like described in Example 2, Example 4 and Example 20 described later.
- the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but preferably, for example, 1,4 dioxane, tetrahydrofuran. 1,2-dimethoxyethane, tert butyl methyl ether, cyclopentinolemethinoleatenore, jetinoleethenore, diisopropinoleethenore, dibutinoleethenore, dicyclopentyl ether, benzene, toluene, xylene or a mixture thereof More preferably, for example, 1,2-dimethoxyethane, toluene and the like.
- the halogenating reagent used in this reaction is preferably, for example, chlorine, bromine, iodine, thionyl chloride, thionyl bromide and the like, and more preferably, for example, chlorothionyl.
- the amount of the halogenated reagent used can be increased or decreased as appropriate.
- the halogenated reagent is preferably used in an amount of, for example, 1.0 to 10.0 times moles relative to the compound (9), More preferably, for example, the amount is 1.0 force to 3.0 times mole.
- the reaction temperature usually varies depending on the starting material, solvent, and other reagents used in the reaction, and can be appropriately changed.
- the reaction temperature is preferably 50 ° C to 0 ° C, more preferably 10 °, for example.
- C force is also 30 ° C.
- the reaction time usually varies depending on the starting material, solvent, other reagents used in the reaction, the reaction temperature, and the degree of progress of the reaction, and can be appropriately increased or decreased, but after adding a base, at the above reaction temperature, Preferably, it is, for example, 1 to 10 hours, and more preferably, for example, 1 to 3 hours.
- step 2_8b X carbonyloxy group
- the sulfonylation reagent used in this reaction is preferably methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl, anhydrous methanesulfonic acid, anhydrous p-toluenesulfonic acid, anhydrous trifluoromethanesulfone, for example.
- An acid and the like more preferably, for example, methanesulfonyl chloride and the like.
- the amount of the sulfonylating reagent used can be appropriately increased or decreased.
- compound (9) for example in an amount of 1.0 to 10.0 moles, more preferably
- the base used in this reaction is preferably, for example, pyridine, triethylamine, diisopropylethylamine, and more preferably, for example, triethylamine.
- the amount of the base used can be increased or decreased as appropriate.
- the amount of the base (6) is preferably, for example, 1.0 force to 3.0 times mole, more preferably, 1.2 force. 1.
- the amount is 6 times the molar amount.
- the reaction temperature usually varies depending on the starting material, solvent, and other reagents used in the reaction, and can be appropriately changed.
- the reaction temperature is preferably 50 ° C to 0 ° C, and more preferably 10 °, for example.
- C force is 30 ° C.
- the reaction time usually varies depending on the starting material, solvent, other reagents used in the reaction, reaction temperature, and the degree of progress of the reaction, and can be appropriately increased or decreased. Preferably, it is, for example, 1 to 10 hours, and more preferably, for example, 1 to 5 hours.
- the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not hinder the reaction, but preferably, for example, 1,4-dioxane, Tetrahydrofuran, 1,2-dimethoxyethane, tert-butyl methyl ether, cyclopent Chinoremethino reetenole, jetino reetenole, diisopropino reetenole, dibutino reetenole, dicyclopentyl ether, benzene, toluene, xylene or a mixed solvent thereof, more preferably, for example, tetrahydrofuran, toluene, etc. Mixed solvent.
- the acylating reagent used in this reaction is preferably acetyl chloride, acetic anhydride, propyl chloride, acetyl bromo, etc., more preferably, for example, acetic anhydride, chloro acetyl, etc.
- the amount of the acylolating reagent used can be increased or decreased as appropriate.
- the base used in this reaction is preferably, for example, 4-dimethylaminopyridine, pyridine, triethylamine, diisopropylethylamine, or the like, and more preferably 4-dimethylaminoviridine, triethylamine, or the like.
- the amount of the base used can be increased or decreased as appropriate.
- the amount of the base (6) is preferably, for example, 1.0 power to 3.0 times mole, more preferably, 1.2 power. 1.
- the amount is 6 times the molar amount.
- the amount of 4-dimethylaminopyridine used can be appropriately increased or decreased, it is preferably an amount of, for example, 0.02 to 1.0-fold mole, more preferably, relative to the compound (9). For example, the amount is 0.05 times mole.
- the reaction temperature usually varies depending on the starting material, solvent, and other reagents used in the reaction, and can be changed as appropriate. Preferably, for example, 0 ° C to 100 ° C, more preferably, 10 ° C, for example. To 50 ° C.
- the reaction time usually varies depending on the starting material, solvent, other reagents used in the reaction, reaction temperature, and the degree of progress of the reaction, and can be appropriately increased or decreased, but after adding a base, at the above reaction temperature, Preferably, it is, for example, 1 to 20 hours, and more preferably, for example, 1 to 5 hours.
- the production method is a step of converting a compound represented by the formula (9) having a hydroxyl group into a compound (10) having a leaving group X, for example, when X is a halogen atom , (2-8a)
- Step 2-8b when X is a sulfonyloxy group (step 2-8b)), when X is an acyloxy group
- the leaving group X is not limited to a halogen atom, a sulfonoxy group, or an acyloxy group.
- synthesis and reaction of organic compounds [1] (page 114) Can be converted into various leaving groups depending on the reaction reagents and reaction conditions described in the above.
- compounds (10-a), (10-b) and (10-a), (10_b) and (10_c) 10—c) is a novel compound.
- the production method has the formula (10) (for example, when X is a halogen atom or a sulfonyloxy group,
- the compound (10-a) is used, and when X is an acyloleoxy group, the compound (10-b) is used.
- This is referred to as the step of converting to the compound (8) by treating with a base (hereinafter referred to as 2-9). ).
- Steps 2-9) can be performed by commonly used methods described in New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds [1] (pages 114-157). More specifically, this step can be performed with reference to the reaction conditions, post-reaction operations, purification methods and the like described in Example 3, Example 4 or Example 20 described later.
- the product can be produced by the method described in Example 2, Example 4 or Example 20 described later.
- the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not hinder the reaction, but preferably, for example, 1,4-dioxane, Tetrahydrofuran, Tetrahydropyran, 1,2-Dimethoxyethane, tert-Butinolemethinoleethenore, Cyclopentinolemethinoleethenore, Jetinoreethenore, Diisopropinoleethenore, Dibutylether, Dicyclopentylether, Benzene , Toluene, xylene or a mixed solvent thereof, more preferably, for example, tetrahydrofuran or toluene.
- the base used in this reaction is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, hydrogen carbonate, for example.
- the amount of the base used can be increased or decreased as appropriate.
- the base is preferably added to the compound (10), preferably ⁇ , ⁇ 0 0. More preferably ⁇ , ⁇ ⁇ ⁇ ⁇ . 0 force etc. 4.0 times mole amount.
- the reaction temperature usually varies depending on the starting materials, the solvent, and other reagents used in the reaction, and can be appropriately changed.
- the reaction temperature is preferably from 40 ° C to 100 ° C, more preferably, for example, 30 °.
- C force is 80 ° C.
- the reaction time usually varies depending on the starting material, solvent, other reagents used in the reaction, reaction temperature, and the degree of progress of the reaction, and can be appropriately increased or decreased, but after adding a base, at the above reaction temperature, Preferably, it is, for example, 10 minutes to 5 hours, more preferably, for example, 10 minutes to 3 hours.
- the compound represented by the formula (9) is reacted with a leaving group-introducing reagent such as a halogenated reagent, a sulfonylating reagent, or an acylating reagent, if necessary, in the presence of a base to obtain a compound.
- a leaving group-introducing reagent such as a halogenated reagent, a sulfonylating reagent, or an acylating reagent, if necessary, in the presence of a base to obtain a compound.
- a leaving group-introducing reagent such as a halogenated reagent, a sulfonylating reagent, or an acylating reagent, if necessary, in the presence of a base to obtain a compound.
- Formula (10) for example, when X is a halogen atom or a sulfonyloxy group, the compound (10
- the compound represented by the formula (8) can also be derived by treating with a base without isolation.
- the production method comprises reacting a compound represented by formula (3) with a compound represented by formula (20) in the presence of a base (according to the description in claim 21). It is referred to as a step (hereinafter referred to as 3 10) step of converting to a compound represented by ).
- Steps 3-10) can be carried out by commonly used methods such as those described in New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds [1] (page 511 also page 534). More specifically, this step can be performed with reference to the reaction conditions, post-reaction operations, purification methods and the like described in Examples 18 and 19 described later.
- the compound represented by the formula (20) for example, a compound that can be produced by the method described in Reference Example 1 or Example 19 can be used.
- the compound (10-a) represented by the formula (20-a) is a novel compound.
- the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not hinder the reaction, but preferably 1, 4 dioxane, tetrahydrofuran, for example. 1,2-dimethoxyethane, tert butyl methyl ether, cyclopentyl methyl ether, jetyl ether, diisopropyl ether, dibutyl ether, dicyclopentyl ether, benzene, toluene, xylene, n-hexane, c-hexane, or these A mixed solvent of tetrahydrofuran and toluene, for example, is more preferable.
- the base is preferably a lithium amide such as n_butyllithium, see butyllithium, tert_butyllithium or lithium diisopropylamide, 2, 2, 6, 6-tetramethylpiperidine lithium amide, more preferably For example, lithium diisopropylamide.
- the amount of compound (20) used can be increased or decreased as appropriate, but is preferably 0.9 times the amount of compound (3), more preferably 0.0 times monolear relative to compound (3). Is the amount of 0.9 power and 1.5 times monore.
- compound (3) is treated with a base, and compound (20) is reacted in the next step.
- compound (3) is treated with a base, and compound (20) is reacted in the next step.
- the reaction temperature between the compound (3) and the base is usually determined from the starting materials, solvents, and other reactions used in the reaction. The setting varies depending on the drug and can be changed as appropriate.
- 0 ° C more preferably, for example, -70 ° C to -30 ° C.
- the reaction time between the compound (3) and the base usually varies depending on the starting material, solvent, other reagents used in the reaction, reaction temperature and reaction rate, and can be increased or decreased as appropriate.
- the reaction temperature is preferably, for example, 10 minutes to 3 hours, more preferably 20 minutes to 1 hour, for example.
- reaction temperature between the base-treated compound represented by formula (3) and the compound represented by formula (20) is:
- the reaction time between the base-treated compound represented by formula (3) and the compound represented by formula (20) usually varies depending on the starting material, solvent, other reagents used in the reaction, and the reaction temperature. After adding the base, the reaction temperature is preferably, for example, 10 minutes to 5 hours, more preferably, for example, 20 minutes to 2 hours.
- This production method is referred to as a step of converting the compound represented by formula (21) into the compound represented by formula (9) by treating with a reducing agent (hereinafter referred to as 3-11). ).
- the reaction in this step is preferably performed in the presence of a solvent.
- it can be performed under an inert gas stream such as nitrogen or argon (or under an atmosphere such as nitrogen or argon).
- the compound represented by the formula (21) can be produced by the methods described in Examples 18 and 19 described later.
- the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not hinder the reaction.
- isopropyl alcohol, ethanol Use an alcohol solvent such as methanol, an ether solvent such as tetrahydrofuran, 1,2_dimethoxetane, jetyl ether, dioxane, a hydrocarbon solvent such as benzene, toluene, hexane, or a mixed solvent thereof.
- Preferable examples include tetrahydrofuran, isopropyl alcohol, benzene, and toluene.
- the reducing reagent means, for example, metal hydrides such as dialkylaluminum hydride, alkali metal borohydride and alkali metal hydride, boron compounds such as borane and alkylborane.
- metal hydrides such as dialkylaluminum hydride, alkali metal borohydride and alkali metal hydride
- boron compounds such as borane and alkylborane.
- the reducing reagent include, for example, diisobutyranolenominum hydride, sodium borohydride, lithium aluminum hydride, diborane and the like, and more preferable examples include, for example, sodium borohydride. Can be raised.
- the amount of the reducing agent to be used can be appropriately increased or decreased, but is preferably 0.5 to 10.1 times the amount of the compound (21), more preferably, to the compound (21). For example, it is 0.5 force and 1.5 times the amount of monole.
- the reaction temperature between the compound (21) and the reducing agent usually varies depending on the starting material, the solvent, and other reagents used in the reaction, and can be changed as appropriate. 40 ° C, more preferably, for example, 0 ° C to 30 ° C.
- the reaction time between the compound (21) and the reducing agent usually varies depending on the starting material, solvent, other reagents used in the reaction, reaction temperature and reaction rate, and can be increased or decreased as appropriate. Thereafter, the reaction temperature is preferably, for example, 10 minutes to 24 hours, more preferably 20 minutes to 13 hours.
- the compound represented by the formula (9) obtained by the above step is obtained by the formula (10) according to the steps 2-8a), 2_8b) or 2_8c) described in the above production method 2.
- X is a halogen atom or a sulfonyloxy group
- the compound (10_a) is a halogen atom or a sulfonyloxy group, the compound (10_a), X
- step 2-9 The compound represented by the above-mentioned step 2-9) is treated with a base to give compound (8).
- the production method comprises the step of converting to the compound (12) by reacting the compound represented by the formula (11) with the compound represented by the formula (1) in the presence of a reducing agent (hereinafter referred to as 412) That's it. ).
- a reducing agent hereinafter referred to as 412
- Steps 4-12 can be carried out by commonly used methods described in New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds [III] (pages 1380 to 1387). More specifically, this step can be performed with reference to the reaction conditions, post-reaction operations, purification methods and the like described in Example 11 described later.
- the compound represented by the formula (11) is a known compound, a commercially available compound, or a compound that can be easily produced from a commercially available compound by a method that is usually performed by those skilled in the art. Can do.
- the solvent used in the reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but as a specific example, for example, tetrahydrofuran, 1,2-dimethoxyethane, jetinoreethenole, ether solvents such as dioxane, hydrocarbon solvents such as benzene, toluene, hexane, ethyl acetate, methanol or a mixed solvent thereof, more preferably For example, tetrahydrofuran, benzene, and toluene.
- the compound (1) is preferably, for example, 1.0 to 5.0 times mol, more preferably 1.0 to 1.5 times mol, of the compound (11).
- the reducing reagent is preferably diisobutylaluminum hydride, cyanoborohydride, for example.
- the amount of the reducing reagent used can be increased or decreased as appropriate, but is preferably up to 10%, more preferably 10 times the amount of the monole, compared to compound (11). ⁇ , ⁇ ⁇ ⁇ ⁇ ⁇ 3. The amount of monolith is 0 times.
- the reaction temperature is not particularly limited, but usually varies depending on the starting material, solvent, and other reagents used in the reaction, and can be appropriately changed. Preferably, for example, 0 ° C to 80 ° C, more preferably Is, for example, 10 ° C to 30 ° C.
- the reaction time is not particularly limited, but usually varies depending on the starting material, solvent, other reagents used in the reaction, reaction temperature, and the degree of progress of the reaction.
- the reaction temperature is preferably, for example, 1 to 10 hours, more preferably about 2 hours, for example.
- the reductive amination reaction can be carried out in a buffer in the presence of a catalyst such as acetic acid or ammonium acetate, if necessary.
- This production method is referred to as a step of converting the compound represented by formula (12) into a compound (13) by heating in the presence of an acid (hereinafter referred to as 413). ).
- Steps 4-13) can be carried out by commonly used methods described in New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds [II] (pages 1134 to 1220). More specifically, this step can be performed with reference to the reaction conditions, post-reaction operations, purification methods and the like described in Example 12 described later.
- the compound represented by the formula (12) is a compound that can be produced by a method described in Example 11, etc. described later, a known compound, a commercially available compound, or a commercially available compound. A compound that can be easily produced by a method commonly used by a trader can be used.
- the solvent used in the heating reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but as a specific example, preferably, for example, 4_dioxane, tetrahydrofuran, 1,2-dimethoxyethane, tert-butinolemethinoleatenore, cyclopentinolemethinoleatenore, jetinoleotenole, diisopropylpropenoate, dibutyl ether, dicyclopentyl ether, N, N dimethylformamide, N —Methylpyrrolidone, acetonitrile, dimethyl sulfoxide, benzene, toluene, xylene, acetic acid and the like, more preferably, for example, acetic acid.
- the reaction temperature is not particularly limited, but usually varies depending on starting materials, solvents, and other reagents used in the reaction, and can be appropriately changed. Preferably, for example, from 50 ° C
- C force is 150 ° C.
- the reaction time is not particularly limited, but usually varies depending on the starting material, solvent, other reagents used in the reaction, reaction temperature, and the degree of progress of the reaction, but can be appropriately increased or decreased. More preferably, the reagent is added. At the above reaction temperature, preferably for 1 to 24 hours, for example.
- the production method comprises hydrolyzing the compound represented by formula (13) in the presence of a base.
- Steps 4-14 can be performed by commonly used methods such as those described in New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds [II] (pages 921 to 1000). More specifically, this step can be performed with reference to the reaction conditions, post-reaction operations, purification methods and the like described in Example 12 described later.
- the compound represented by the formula (13) can be produced by a method described in Example 11 and the like described later.
- the solvent used in the reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but as a specific example, for example, methanol is preferable. , ethanol, propanol, ⁇ , 4 _ Jiokisan, tetrahydrofuran, 1, 2_ dimethoxyethane Kishetan, tert-butyl methyl ether, cyclopentyl methyl ether, Jechi Noreetenore, diisopropylidene Honoré ether Honoré, dibutyl Honoré ether Honoré, dicyclopentyl Honoré ether, Acetonitrile, water, or a mixed solvent thereof, and more preferably, for example, methanol, ethanol, or a mixed solvent of these with water.
- the base used in this reaction is preferably lithium hydroxide, sodium hydroxide, water, for example.
- Potassium oxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, cesium chloride, imidazole, pyridine, 4-dimethylaminopyridine, triethinoreamine, N, N diisopropylene Tyramine, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and the like can be used, and for example, sodium hydroxide, potassium hydroxide and the like are more preferable.
- the base is preferably used in an amount of, for example, 1.0 to 10.0 moles, more preferably 1.0 mole to 5.0 moles, relative to Compound (13).
- the reaction temperature is not particularly limited, but usually varies depending on starting materials, solvents, and other reagents used in the reaction, and can be appropriately changed.
- 10 ° C to 50 ° C Preferably, for example, 10 ° C force is 30 ° C.
- the reaction time is not particularly limited, but usually varies depending on the starting material, solvent, other reagents used in the reaction, reaction temperature, and the degree of progress of the reaction, but can be appropriately increased or decreased.
- the reaction temperature is preferably, for example, 1 to 24 hours, more preferably, for example, about 2 hours.
- the production method is referred to as a step of converting to a compound (8) (hereinafter referred to as 4 to 15) by reacting the compound represented by the formula (14) and the compound represented by the formula (7) in the presence of a base. . ).
- the compound represented by the formula (14) can be produced by a method described in Example 12 and the like described later.
- the compound represented by the formula (7) can be produced, for example, by the method described in Reference Example 1. it can.
- the solvent used in the reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but as a specific example, for example, methanol is preferable.
- the base used in this reaction is preferably pyrrolidine, piperidine, pyridine or the like.
- the base is preferably used in an amount of, for example, 1.0 to 10.0-fold mol, more preferably 1.0-fold to 3.0-fold mol, with respect to Compound (14).
- the reaction temperature usually varies depending on the starting materials, solvent, and other reagents used in the reaction, and can be changed as appropriate.
- the reaction temperature is, for example, 50 ° C to 150 ° C, and more preferably, For example, 50 ° C force is 80 ° C.
- the reaction time is not particularly limited, but usually varies depending on the starting material, solvent, other reagents used in the reaction, reaction temperature, and the degree of progress of the reaction, but can be appropriately increased or decreased.
- At the reaction temperature preferably for example 1 to 48 hours, more preferably
- R represents a 6- to 14-membered aromatic hydrocarbon ring group which may have a substituent or a 5- to 14-membered aromatic heterocyclic group which may have a substituent
- Q represents a single group.
- a synthetic intermediate for producing the compound of formula (8) with good yield and a production method thereof.
- Methyl iodide (463 g) was added dropwise at room temperature to a DMF (1 L) mixture of 3 hydroxy-4-nitrobenzoic acid (199 g) and potassium carbonate (450 g). The reaction solution was stirred at room temperature overnight, methyl iodide (230 g) was added to the reaction solution, and the reaction solution was further stirred at room temperature for 6 hours. The reaction solution was added to ice water, and the precipitated solid was collected by filtration. The obtained solid was dried at 50 ° C. overnight to obtain 178 g of the title compound. The physical properties agreed with the reported values (CAS # 5081—37—8).
- reaction solution was added dropwise to a solution of 3-methoxy-4- (4-methyl-1H-imidazole-1yl) benzoic acid methyl ester (20 g) in THF (50 mL) over 30 minutes under ice cooling.
- the reaction solution was stirred at room temperature for 2 hours, and then 5N aqueous sodium hydroxide solution (150 mL) was added dropwise to the reaction solution.
- Ethyl acetate was added to the reaction solution, and the organic layer was separated. The organic layer was washed with a saturated aqueous ammonium chloride solution and saturated brine in this order.
- the organic layer was dried over anhydrous magnesium sulfate and filtered on a silica gel pad, and the filtrate was concentrated under reduced pressure.
- the residue was diluted with ethyl acetate, and the precipitated solid was collected by filtration.
- the obtained solid was air-dried overnight to obtain 7.10 g of the title compound.
- the crystallization mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: heptane monoacetate_2_propanol system) to obtain 2.65 g of the title compound.
- reaction solution was cooled to 70 ° C or lower, stirred for 30 minutes, and then added to this reaction mixture with 1- [1- (4 fluorophenyl) ethyl] piperidine-2-one (10 g, 45.2 mol).
- Toluene (50 mL) solution was added dropwise over 30 minutes.
- To the reaction mixture was added dropwise a solution of 3-methoxy-4-mono (4-methylimidazole-1-inole) benzanaldehyde (9.75 g, 45. lmmol, 1.0 eq) in tetrahydrofuran (12 OmL) over 30 minutes.
- the temperature of the cooling bath was raised to about ⁇ 40 ° C., and then water (20 mL) was added to complete the reaction.
- the reaction solution was further heated to room temperature.
- Water (30 mL) was added to the reaction mixture, transferred to a separator, and the aqueous layer was discarded.
- 2N-hydrochloric acid was added to the organic layer to adjust the pH of the aqueous layer to 1.0, and the aqueous layer was separated. Tetrahydrofuran and 2N-sodium hydroxide aqueous solution were added to this aqueous layer to make ⁇ 0.0, and the aqueous layer was discarded.
- Toluene was added to the organic layer, washed sequentially with 5% brine and water, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain 19.186 g of a crude product as a dark brown oil. .
- toluene 140 mL was added to the reaction mixture cooled in an ice-water bath, followed by addition of 2N aqueous sodium hydroxide solution (140 mU).
- the reaction solution was transferred to a separatory funnel and the aqueous layer was discarded, and the organic layer was washed successively with 5% brine (2 ⁇ 66 mL), water (5 mL), and dried over anhydrous magnesium sulfate.
- the solvent was concentrated under reduced pressure to obtain 22. lg of the crude product as a brown oil.
- the title compound is 1 [1 4 fluorophenyl) ethyl] 3- ⁇ hydroxy [3-methoxy-4- (4-methylimidazole-1-yl) phenyl] methyl ⁇ piperidin-2-one (1.6 g 3.68 mmol)
- salt ⁇ thioninole 538 xL 7.36 mol, 2 equivalents
- stir for 1.5 hours and pour into ice-cold saturated aqueous sodium bicarbonate solution.
- Extracted with ethyl acetate washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 1.68 g.
- 1,8-diazabicyclo [5.4.0] unde_7_cene (105 mg, 0.887 mol) was added to the reaction solution, and the reaction solution was heated to 100 ° C. After stirring the reaction solution for 3 hours, water was added and the mixture was entangled and extracted with ethyl acetate. The organic layer was washed with water, then with saturated brine, further dried over magnesium sulfate, and concentrated under reduced pressure to obtain about 66 mg of the title compound.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06832861A EP1950211A4 (en) | 2005-11-18 | 2006-11-17 | PROCESS FOR PREPARING A CINEMA ACID AMID DERIVATIVE |
AU2006316005A AU2006316005A1 (en) | 2005-11-18 | 2006-11-17 | Process for production of cinnamamide derivative |
CA002628047A CA2628047A1 (en) | 2005-11-18 | 2006-11-17 | Process for production of cinnamide derivative |
US12/093,287 US20090270623A1 (en) | 2005-11-18 | 2006-11-17 | Process for production of cinnamide derivative |
JP2007545314A JPWO2007058305A1 (ja) | 2005-11-18 | 2006-11-17 | シンナミド誘導体の製造方法 |
IL191125A IL191125A0 (en) | 2005-11-18 | 2008-04-28 | Process for production of cinnamide derivative |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2005334286 | 2005-11-18 | ||
JP2005-334286 | 2005-11-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2007058305A1 true WO2007058305A1 (ja) | 2007-05-24 |
Family
ID=38048688
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2006/322982 WO2007058305A1 (ja) | 2005-11-18 | 2006-11-17 | シンナミド誘導体の製造方法 |
Country Status (9)
Country | Link |
---|---|
US (1) | US20090270623A1 (ja) |
EP (1) | EP1950211A4 (ja) |
JP (1) | JPWO2007058305A1 (ja) |
KR (1) | KR20080076907A (ja) |
CN (1) | CN101309916A (ja) |
AU (1) | AU2006316005A1 (ja) |
CA (1) | CA2628047A1 (ja) |
IL (1) | IL191125A0 (ja) |
WO (1) | WO2007058305A1 (ja) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008140111A1 (ja) * | 2007-05-16 | 2008-11-20 | Eisai R & D Management Co., Ltd. | シンナミド誘導体のワンポット製造方法 |
WO2009061699A1 (en) * | 2007-11-05 | 2009-05-14 | Schering Corporation | Gamma secretase modulators |
US7897627B2 (en) | 2007-12-21 | 2011-03-01 | Hoffmann-La Roche Inc. | Heteroaryl derivatives as orexin receptor antagonists |
US7910740B2 (en) | 2007-05-11 | 2011-03-22 | Hoffmann-La Roche Inc. | Modulators of amyloid beta |
US7923450B2 (en) | 2008-01-11 | 2011-04-12 | Hoffmann-La Roche Inc. | Modulators for amyloid beta |
US7923563B2 (en) | 2004-10-26 | 2011-04-12 | Eisai R&D Management Co., Ltd. | Amorphous object of cinnamide compound |
US8288403B2 (en) | 2008-11-10 | 2012-10-16 | Hoffmann-La Roche Inc. | Heterocyclic gamma secretase modulators |
US8367863B2 (en) | 2007-12-20 | 2013-02-05 | Envivo Pharmaceuticals, Inc. | Tetrasubstituted benzenes |
US8389717B2 (en) | 2008-10-09 | 2013-03-05 | Hoffmann-La Roche Inc. | Modulators for amyloid beta |
US8486967B2 (en) | 2010-02-17 | 2013-07-16 | Hoffmann-La Roche Inc. | Heteroaryl substituted piperidines |
US8962834B2 (en) | 2008-02-22 | 2015-02-24 | Hoffmann-La Roche Inc. | Modulators of amyloid beta |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI335816B (en) * | 2004-05-26 | 2011-01-11 | Eisai R&D Man Co Ltd | Cinnamide compound |
EP1953151A4 (en) * | 2005-11-18 | 2010-06-02 | Eisai R&D Man Co Ltd | SALTS FROM A CYNNAMIDE COMPOUND OR SOLVATE THEREOF |
TWI370130B (en) * | 2005-11-24 | 2012-08-11 | Eisai R&D Man Co Ltd | Two cyclic cinnamide compound |
KR20080069221A (ko) * | 2005-11-24 | 2008-07-25 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 모르폴린 타입의 신나미드 화합물 |
TWI378091B (en) * | 2006-03-09 | 2012-12-01 | Eisai R&D Man Co Ltd | Multi-cyclic cinnamide derivatives |
KR20090018963A (ko) * | 2006-05-19 | 2009-02-24 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 우레아계 신나미드 유도체 |
EP2019094A4 (en) * | 2006-05-19 | 2011-01-05 | Eisai R&D Man Co Ltd | HETEROCYCLIC TYPE CINNAMIDE DERIVATIVE |
US7737141B2 (en) * | 2006-07-28 | 2010-06-15 | Eisai R&D Management Co., Ltd. | Prodrug of cinnamide compound |
DE102007009810A1 (de) * | 2007-02-28 | 2008-09-04 | Man Roland Druckmaschinen Ag | Übertragungsform für einen Übertragungszylinder einer Druckmaschine |
PE20081791A1 (es) * | 2007-02-28 | 2009-02-07 | Eisai Randd Man Co Ltd | Dos derivados ciclicos de oxomorfolina |
JP2010524844A (ja) * | 2007-04-26 | 2010-07-22 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 認知症のためのシンナミド化合物 |
US7935815B2 (en) * | 2007-08-31 | 2011-05-03 | Eisai R&D Management Co., Ltd. | Imidazoyl pyridine compounds and salts thereof |
CA2694401C (en) | 2007-08-31 | 2012-12-04 | Eisai R&D Management Co., Ltd. | Polycyclic compound |
CN101925607A (zh) * | 2008-01-28 | 2010-12-22 | 卫材R&D管理有限公司 | 结晶性的肉桂酰胺化合物或其盐 |
US20110190269A1 (en) | 2010-02-01 | 2011-08-04 | Karlheinz Baumann | Gamma secretase modulators |
US20220089620A1 (en) * | 2019-01-27 | 2022-03-24 | Board Of Regents, The University Of Texas System | Inhibitors of the enzyme enolase for precision oncology |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS521035A (en) * | 1975-06-19 | 1977-01-06 | Nelson Res & Dev | Vihicle composition containing 11substituted azacycloalkanee22 one |
JPH09132578A (ja) * | 1995-09-12 | 1997-05-20 | F Hoffmann La Roche Ag | セファロスポリン誘導体 |
JPH11513686A (ja) * | 1995-10-19 | 1999-11-24 | メルク エンド カンパニー インコーポレーテッド | 線維素原受容体拮抗薬 |
WO2004041776A2 (en) * | 2002-05-06 | 2004-05-21 | Bristol-Myers Squibb Company | SULFONYLAMINOVALEROLAC TAMS AND DERIVATIVES THEREOF AS FACTOR Xa INHIBITORS |
JP2004536084A (ja) * | 2000-11-06 | 2004-12-02 | ブリストル−マイヤーズ スクイブ ファーマ カンパニー | 因子Xa阻害剤としての単環式又は二環式炭素環及び複素環 |
WO2005087767A1 (en) * | 2004-03-09 | 2005-09-22 | Merck & Co., Inc. | Hiv integrase inhibitors |
WO2005115990A1 (ja) * | 2004-05-26 | 2005-12-08 | Eisai R & D Management Co., Ltd. | シンナミド化合物 |
WO2006046575A1 (ja) * | 2004-10-26 | 2006-05-04 | Eisai R & D Management Co., Ltd. | シンナミド化合物の非晶質体 |
Family Cites Families (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1101156A (en) * | 1965-09-22 | 1968-01-31 | Hickson & Welch Ltd | Triazole derivatives and their use as optical whitening agents |
US3989816A (en) * | 1975-06-19 | 1976-11-02 | Nelson Research & Development Company | Vehicle composition containing 1-substituted azacycloheptan-2-ones |
EP0219756B1 (de) * | 1985-10-09 | 1994-01-05 | Shell Internationale Researchmaatschappij B.V. | Neue Acrylsäureamide |
IT1205834B (it) * | 1987-04-22 | 1989-03-31 | Elbart | Derivati tiodiossolanici ad attivita' mucolitica a procedimento per la loro preparazione |
US5281626A (en) * | 1990-02-08 | 1994-01-25 | Eisai Co., Ltd. | Benzenesulfonamide derivatives |
PT620225E (pt) * | 1993-04-16 | 2003-03-31 | Basilea Pharmaceutica Ag | Derivados de cefalosporina |
AU680870B2 (en) * | 1993-04-28 | 1997-08-14 | Astellas Pharma Inc. | New heterocyclic compounds |
US5538985A (en) * | 1994-01-27 | 1996-07-23 | Mitsui Toatsu Chemicals, Inc. | Pyrrolidinone derivatives |
TR199802282T2 (xx) * | 1996-05-10 | 1999-03-22 | Icos Corporation | Karbolin t�revleri. |
GB9704499D0 (en) * | 1997-03-05 | 1997-04-23 | Glaxo Wellcome Spa | Method of manufacture |
PT916656E (pt) * | 1997-11-14 | 2004-02-27 | Schering Ag | Metodo para producao de derivados de pirrolidinona |
ATE261730T1 (de) * | 1997-12-31 | 2004-04-15 | Univ Kansas | Wasserlösliche medikamentenvorstufen tertiärer amine enthaltender medikamente und verfahren zu ihrer herstellung |
US6235728B1 (en) * | 1999-02-19 | 2001-05-22 | Bristol-Myers Squibb Company | Water-soluble prodrugs of azole compounds |
US7053087B1 (en) * | 1999-03-04 | 2006-05-30 | Cardiome Pharma Corp. | Aminocycloalkyl cinnamide compounds for arrhythmia and analgesics and anesthetics |
US6440414B1 (en) * | 1999-10-01 | 2002-08-27 | Amgen Inc. | Pharmaceutical compositions of fibrinolytic agent |
US6331184B1 (en) * | 1999-12-10 | 2001-12-18 | Scimed Life Systems, Inc. | Detachable covering for an implantable medical device |
US20040087798A1 (en) * | 2000-03-14 | 2004-05-06 | Akira Yamada | Novel amide compounds |
US20010051642A1 (en) * | 2000-04-17 | 2001-12-13 | Kyunghye Ahn | Method for treating Alzheimer's disease |
IL155999A0 (en) * | 2000-12-04 | 2003-12-23 | Hoffmann La Roche | Phenylethenyl or phenylethinyl derivatives as glutamate receptor antagonists |
GB0108770D0 (en) * | 2001-04-06 | 2001-05-30 | Eisai London Res Lab Ltd | Inhibitors |
PL373484A1 (en) * | 2001-12-10 | 2005-09-05 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments |
BR0215182A (pt) * | 2001-12-20 | 2004-10-19 | Bristol Myers Squibb Co | Derivados de (alfa)- (n-sulfonamido) acetamida como inibidores de (beta)-amilóide |
DE60335635D1 (de) * | 2002-05-22 | 2011-02-17 | Amgen Inc | Aminopyrimidin-derivate zur verwendung als vanilloid-rezeptor-liganden zur behandlung von schmerzen |
JP4568603B2 (ja) * | 2002-05-31 | 2010-10-27 | プロテオテック・インコーポレイテッド | アミロイド疾患およびシヌクレイノパチー(例えばアルツハイマー病、タイプ2型糖尿病、およびパーキンソン病)を処置するための化合物、組成物、および方法 |
NZ537603A (en) * | 2002-07-12 | 2006-09-29 | Sanofi Aventis Deutschland | Heterocyclically substituted benzoylureas, method for their production and their use as medicaments |
US6900354B2 (en) * | 2002-07-15 | 2005-05-31 | Hoffman-La Roche Inc. | 3-phenyl-propionamido, 3-phenyl-acrylamido and 3-phenyl-propynamido derivatives |
EP1594847A2 (en) * | 2003-02-12 | 2005-11-16 | Transtech Pharma, Inc. | Substituted azole derivatives as therapeutic agents |
BRPI0410348A (pt) * | 2003-05-14 | 2006-05-30 | Torreypines Therapeutics Inc | compostos e usos dos mesmos na modulação de amilóide-beta |
AU2004268621C1 (en) * | 2003-08-29 | 2011-08-18 | Exelixis, Inc. | c-Kit modulators and methods of use |
CA2551909C (en) * | 2004-02-12 | 2011-10-11 | Transtech Pharma, Inc. | Substituted azole derivatives, compositions, and methods of use |
EP1953151A4 (en) * | 2005-11-18 | 2010-06-02 | Eisai R&D Man Co Ltd | SALTS FROM A CYNNAMIDE COMPOUND OR SOLVATE THEREOF |
KR20080069221A (ko) * | 2005-11-24 | 2008-07-25 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 모르폴린 타입의 신나미드 화합물 |
US20070117839A1 (en) * | 2005-11-24 | 2007-05-24 | Eisai R&D Management Co., Ltd. | Two cyclic cinnamide compound |
TWI378091B (en) * | 2006-03-09 | 2012-12-01 | Eisai R&D Man Co Ltd | Multi-cyclic cinnamide derivatives |
US7737141B2 (en) * | 2006-07-28 | 2010-06-15 | Eisai R&D Management Co., Ltd. | Prodrug of cinnamide compound |
CA2686754C (en) * | 2007-05-11 | 2014-10-28 | F. Hoffmann-La Roche Ag | Hetarylanilines as modulators for amyloid beta |
-
2006
- 2006-11-17 AU AU2006316005A patent/AU2006316005A1/en not_active Abandoned
- 2006-11-17 WO PCT/JP2006/322982 patent/WO2007058305A1/ja active Application Filing
- 2006-11-17 EP EP06832861A patent/EP1950211A4/en not_active Withdrawn
- 2006-11-17 US US12/093,287 patent/US20090270623A1/en not_active Abandoned
- 2006-11-17 JP JP2007545314A patent/JPWO2007058305A1/ja not_active Abandoned
- 2006-11-17 CA CA002628047A patent/CA2628047A1/en not_active Abandoned
- 2006-11-17 KR KR1020087011787A patent/KR20080076907A/ko not_active Application Discontinuation
- 2006-11-17 CN CNA2006800431097A patent/CN101309916A/zh active Pending
-
2008
- 2008-04-28 IL IL191125A patent/IL191125A0/en unknown
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS521035A (en) * | 1975-06-19 | 1977-01-06 | Nelson Res & Dev | Vihicle composition containing 11substituted azacycloalkanee22 one |
JPH09132578A (ja) * | 1995-09-12 | 1997-05-20 | F Hoffmann La Roche Ag | セファロスポリン誘導体 |
JPH11513686A (ja) * | 1995-10-19 | 1999-11-24 | メルク エンド カンパニー インコーポレーテッド | 線維素原受容体拮抗薬 |
JP2004536084A (ja) * | 2000-11-06 | 2004-12-02 | ブリストル−マイヤーズ スクイブ ファーマ カンパニー | 因子Xa阻害剤としての単環式又は二環式炭素環及び複素環 |
WO2004041776A2 (en) * | 2002-05-06 | 2004-05-21 | Bristol-Myers Squibb Company | SULFONYLAMINOVALEROLAC TAMS AND DERIVATIVES THEREOF AS FACTOR Xa INHIBITORS |
WO2005087767A1 (en) * | 2004-03-09 | 2005-09-22 | Merck & Co., Inc. | Hiv integrase inhibitors |
WO2005115990A1 (ja) * | 2004-05-26 | 2005-12-08 | Eisai R & D Management Co., Ltd. | シンナミド化合物 |
WO2006046575A1 (ja) * | 2004-10-26 | 2006-05-04 | Eisai R & D Management Co., Ltd. | シンナミド化合物の非晶質体 |
Non-Patent Citations (1)
Title |
---|
LUTZ FRIEDJAN TIETZE ET AL.: "Jikken Manual", vol. 2ND ED., 15 January 1995, NANKODO CO., LTD., pages: 196 - 199, XP003009081 * |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7923563B2 (en) | 2004-10-26 | 2011-04-12 | Eisai R&D Management Co., Ltd. | Amorphous object of cinnamide compound |
US7910740B2 (en) | 2007-05-11 | 2011-03-22 | Hoffmann-La Roche Inc. | Modulators of amyloid beta |
WO2008140111A1 (ja) * | 2007-05-16 | 2008-11-20 | Eisai R & D Management Co., Ltd. | シンナミド誘導体のワンポット製造方法 |
US8487099B2 (en) | 2007-11-05 | 2013-07-16 | Merck Sharp & Dohme Corp. | Gamma secretase modulators |
WO2009061699A1 (en) * | 2007-11-05 | 2009-05-14 | Schering Corporation | Gamma secretase modulators |
US8367863B2 (en) | 2007-12-20 | 2013-02-05 | Envivo Pharmaceuticals, Inc. | Tetrasubstituted benzenes |
US8664249B2 (en) | 2007-12-20 | 2014-03-04 | Envivo Pharmaceuticals, Inc. | Tetrasubstituted benzenes |
US7897627B2 (en) | 2007-12-21 | 2011-03-01 | Hoffmann-La Roche Inc. | Heteroaryl derivatives as orexin receptor antagonists |
US7923450B2 (en) | 2008-01-11 | 2011-04-12 | Hoffmann-La Roche Inc. | Modulators for amyloid beta |
US8962834B2 (en) | 2008-02-22 | 2015-02-24 | Hoffmann-La Roche Inc. | Modulators of amyloid beta |
US8389717B2 (en) | 2008-10-09 | 2013-03-05 | Hoffmann-La Roche Inc. | Modulators for amyloid beta |
US8288403B2 (en) | 2008-11-10 | 2012-10-16 | Hoffmann-La Roche Inc. | Heterocyclic gamma secretase modulators |
US8486967B2 (en) | 2010-02-17 | 2013-07-16 | Hoffmann-La Roche Inc. | Heteroaryl substituted piperidines |
Also Published As
Publication number | Publication date |
---|---|
US20090270623A1 (en) | 2009-10-29 |
EP1950211A1 (en) | 2008-07-30 |
EP1950211A4 (en) | 2011-08-31 |
IL191125A0 (en) | 2008-12-29 |
CN101309916A (zh) | 2008-11-19 |
JPWO2007058305A1 (ja) | 2009-05-07 |
CA2628047A1 (en) | 2007-05-24 |
KR20080076907A (ko) | 2008-08-20 |
AU2006316005A1 (en) | 2007-05-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2007058305A1 (ja) | シンナミド誘導体の製造方法 | |
JP5624762B2 (ja) | 新規ピロリノン誘導体およびそれを含有する医薬組成物 | |
AU2008249745B2 (en) | Substituted heterocyclic derivatives and compositions and their pharmaceutical use as antibacterials | |
JP6300042B2 (ja) | 癌の処置に使用するための化合物の製造方法 | |
JP4932065B2 (ja) | βセクレターゼ阻害剤としてのラクタム | |
WO2001064670A1 (fr) | Nouveaux derives amide cycliques | |
WO2009125809A1 (ja) | ピペリジン誘導体 | |
CN111484442A (zh) | 一种具有抗肿瘤活性的csf1r抑制剂中间体的制备方法 | |
WO2022107755A1 (ja) | 新規アクリジニウム塩およびその製造方法 | |
JP2020045306A (ja) | ヘテロシクロアルキル環を含むアミド誘導体 | |
WO2009119700A1 (ja) | ピペリジン-3-イルカーバメート化合物の製造方法およびその光学分割方法 | |
JPWO2006123767A1 (ja) | 不斉四置換炭素原子含有化合物の製法 | |
US7842818B2 (en) | Process for preparation of tetrasubstituted 5-azaspiro[2.4]- heptane derivatives and optically active intermediates thereof | |
TW201130488A (en) | Pyrrole compound | |
JP2017519826A (ja) | イブチニブ中間体化合物、その製造方法及び用途 | |
KR101686087B1 (ko) | 광학 활성을 갖는 인돌린 유도체 또는 이의 염의 신규 제조 방법 | |
WO2002089803A1 (en) | Composition for iontophoresis | |
WO2006062063A1 (ja) | ピペリジン誘導体及びその製造法 | |
CA3214107A1 (en) | New process for the synthesis of 5-{5-chloro-2-[(3s)-3- [(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1h)- carbonyl]phenyl}-1,2-dimethyl-1h-pyrrole-3-carboxylic acid derivatives and its application for the production of pharmaceutical compounds | |
TW202003483A (zh) | 二芳基甲烷化合物之製造方法 | |
WO2000061575A1 (fr) | Production de derives indole et intermediaires a cet effet | |
JPWO2008140111A1 (ja) | シンナミド誘導体のワンポット製造方法 | |
JP2002080472A (ja) | アルキルオキシアミノフラノン誘導体の製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200680043109.7 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2007545314 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 191125 Country of ref document: IL |
|
ENP | Entry into the national phase |
Ref document number: 2628047 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 3948/DELNP/2008 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12093287 Country of ref document: US Ref document number: 2006832861 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006316005 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020087011787 Country of ref document: KR |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2006316005 Country of ref document: AU Date of ref document: 20061117 Kind code of ref document: A |