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WO2002034712A1 - Procede de preparation de composes aromatiques substitues et produits intermediaires associes - Google Patents

Procede de preparation de composes aromatiques substitues et produits intermediaires associes

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Publication number
WO2002034712A1
WO2002034712A1 PCT/JP2001/009422 JP0109422W WO0234712A1 WO 2002034712 A1 WO2002034712 A1 WO 2002034712A1 JP 0109422 W JP0109422 W JP 0109422W WO 0234712 A1 WO0234712 A1 WO 0234712A1
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WO
WIPO (PCT)
Prior art keywords
salt
compound
formula
substituent
represented
Prior art date
Application number
PCT/JP2001/009422
Other languages
English (en)
Japanese (ja)
Inventor
Masahiro Mizuno
Mitsuhisa Yamano
Original Assignee
Takeda Chemical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to AU2001296008A priority Critical patent/AU2001296008A1/en
Publication of WO2002034712A1 publication Critical patent/WO2002034712A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/54—Preparation of compounds containing amino groups bound to a carbon skeleton by rearrangement reactions
    • C07C209/58—Preparation of compounds containing amino groups bound to a carbon skeleton by rearrangement reactions from or via amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/08—Preparation of carboxylic acid amides from amides by reaction at nitrogen atoms of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
    • C07D215/60—N-oxides

Definitions

  • the present invention relates to a method for producing a substituted aromatic compound utilizing a Smiles rearrangement reaction and a production intermediate. More specifically, the present invention provides a simple method for producing a substituted aromatic compound as an intermediate for producing pharmaceuticals, agricultural chemicals, or many general-purpose chemicals, which can carry out the Smiles rearrangement reaction under mild and safe conditions. , And intermediates useful in such processes. Background art
  • Smiles rearrangement is a reaction in which an atom bonded to an aromatic ring is replaced with another atom by a nucleophilic substitution reaction in the molecule.
  • carbon and heteroatoms such as nitrogen, oxygen, sulfur, phosphorus and iodine are generally known.
  • the general direction of rearrangement is sulfur to carbon, nitrogen, oxygen, oxygen to carbon, nitrogen, oxygen, sulfur, phosphorus to carbon, and iodine to oxygen.
  • the rearrangement is generally performed in a solvent in the presence of a base.
  • bases and solvents required for the rearrangement have been known so far (Org. React., Vol. 18, p. 99, 1970).
  • an aqueous solution of sodium hydroxide or potassium hydroxide, a methanol solution, an ethanol solution, an acetone solution, a methanol solution of sodium methoxide, or an ethanol solution of sodium methoxide are generally used.
  • the activity of the reaction is low and generally requires a high-temperature reaction, and the reaction may not proceed depending on the substrate.
  • a strong base such as a solution of butyllithium in ether or a solution of sodium hydride in dimethylformamide is used.
  • aromatic compounds are used in the manufacture of pharmaceuticals, pesticides, and many general-purpose chemicals. There are many useful as a body, and various methods for its production are known, including the Smiles rearrangement reaction.
  • an aniline derivative is an important compound that can be used as a chemical or pharmaceutical, and itself is often an important production intermediate.
  • the methods for producing an aniline derivative there are known a few methods for converting from a phenol derivative, but all have drawbacks such as danger and toxicity.
  • a phenol derivative is activated with 4-chloro-2-phenylquinazoline, the rearrangement requires a high temperature of about 300 ° C and basic conditions.
  • getyl chlorophosphate is used, which is potassium metal in liquid ammonia.
  • the Bucherer reaction is limited to heterocycles such as naphthalene and hydroxyquinoline, and is a heated reaction with ammonium sulfite under pressure (Tetrahedron, Vol. 53, pp. 6303, 1997 Year) .
  • Ammonium sulfite under pressure Tetrahedron, Vol. 53, pp. 6303, 1997 Year
  • a phenol derivative to an aniline derivative using the Smiles rearrangement reaction see Journal of the Chemical Society 'Perkin' Transactions ⁇ (J. Chera. Soc. Perkin Trans.
  • 6-aminoquinaldine derivatives are useful as skeletons of chemicals and pharmaceuticals, and as a production method, a method of reducing 6-dito 'mouth quinaldine derivatives is generally used.
  • the problem of the Smiles rearrangement is that the reactivity is low. If the reaction is performed at high temperature to increase the reactivity, it cannot be applied to compounds that are unstable to heat. This means that the atoms of the aromatic ring cannot be easily exchanged, and the advantage of the Smiles rearrangement cannot be used effectively.
  • a strong base such as butyllithium or sodium hydride is used as the base to increase the reactivity, it is necessary to handle with care due to the danger of ignition and the like. It is hard to say that it is suitable as a safe manufacturing method.
  • An object of the present invention is to solve these problems in the Smiles rearrangement reaction and to convert various aromatic compounds useful as intermediates in the production of pharmaceuticals, agricultural chemicals, or many general-purpose chemicals by utilizing the Smiles rearrangement reaction. It is to manufacture efficiently.
  • one object of the present invention is to enable the Smiles rearrangement reaction to be carried out under mild conditions using a safe reagent.
  • Another object of the present invention is to provide a method for producing a phenol derivative from a phenol derivative, which is generally easily available, as a raw material and using a smile-rearrangement reaction under mild conditions to convert the phenol derivative to an ayuline derivative simply. It is to provide.
  • a further object of the present invention is to provide a production method for converting a 6-hydroxy-1-tetralone derivative into a 6-amino-1-tetraporone derivative by utilizing a Smiles rearrangement reaction and a production intermediate thereof. is there.
  • Still another object of the present invention is to use a 6-hydroxyquinanoresin derivative, which is easily available, as a raw material and to utilize the Smiles rearrangement reaction, and simultaneously carry out N-oxidation.
  • An object of the present invention is to provide a production method for easily converting the compound into an -aminoquinaldine N-oxide derivative and a production intermediate thereof.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems.
  • the first problem is that a novel combination of a basic hydroxide and an amide-based solvent provides a mild and safe solution. Under these conditions, we found the conditions under which the Smiles rearrangement reaction proceeds.
  • the third challenge is to use the Smiles rearrangement reaction, starting from a 6-hydroxyl 1-tetralone derivative, via only two new intermediates, At this stage, it was found that a 6-amino-1-tetralone derivative can be produced easily and inexpensively using a safe, nontoxic reagent by a simple and industrially superior method.
  • the 6-hydroxyquinaldine derivative is converted to the N-oxide form to increase the activity of the Smiles rearrangement reaction to increase the activity of the 6-hydroxyminaldine N-oxide derivative. It has been found that it can be manufactured in a simple, industrially superior method using one-pot steps, and using inexpensive, safe and non-toxic reagents.
  • ring A represents an aromatic homo or hetero ring which may have a substituent.
  • X is — O-; one S-; — S (O) one; — S ( ⁇ ) 2- ; one P + R lx R 2 x — (R lx and R 2 x are each a hydrogen atom or a substituent ); ⁇ — or NR 1 — (R represents a hydrogen atom or a substituent), Y is —0—; — S —; — S (O) one; — S (O) 2 —; _P + R lxx R 2xx — (R lxx and R 2xx represents a hydrogen atom or a substituent, respectively; -1 + —; one NR la — (R 1a represents a hydrogen atom or a substituent) or one CR ⁇ 'R 2 ′′ — (R 1 ''And R 2 ''each represent a hydrogen atom or a substituent).
  • B represents an aromatic homo or hetero ring which may have a substituent, or an ethylene group which may be substituted.
  • disulfide compound or a salt thereof represented by the formula (II) is subjected to a Smiles rearrangement reaction.
  • X is one 0_; — S—; — S (O) — or one S (O) 2 —
  • ring A represents an aromatic homo or hetero ring which may have a substituent.
  • Z represents an optionally substituted methylene group, W represents an oxygen atom or a sulfur atom, and R 1 represents a hydrogen atom or a substituent.
  • R 1 represents a hydrogen atom or a substituent.
  • (9) Z is the (6) Symbol mounting method for producing a two _ 4 methylene group substituted by an alkyl group
  • ring A represents an aromatic homo or hetero ring which may have a substituent
  • W represents an oxygen atom or a sulfur atom.
  • a method comprising reacting a compound represented by the formula (VII) or a salt thereof with an alkylating agent represented by the formula (VIII) or a salt thereof in the presence of a basic hydroxide and an amide solvent.
  • ring A represents an aromatic homo or hetero ring which may have a substituent.
  • R 1 represents a hydrogen atom or a substituent.
  • ring A represents an aromatic homo or hetero ring which may have a substituent.
  • R 1 represents a hydrogen atom or a substituent.
  • Z represents a methylene group which may be substituted
  • C-C-C represent a carbon chain which may have a substituent
  • RR 2 , R 2a and R 2b are the same or different.
  • each represents a hydrogen atom or a substituent.
  • the bond of the C-C-C carbon chain may be a single bond or either one may be a double bond.
  • Z represents a methylene group which may be substituted
  • C—C—C represents a carbon chain which may have a substituent
  • RR 2 , R 2a and R 2b are the same or different.
  • Each represents a hydrogen atom or a substituent.
  • the bond of the carbon chain of cc-c may be a single bond or either one may be a double bond.
  • C—C—C represents a carbon chain which may have a substituent
  • R 2 , R 2a and R 2b are the same or different and each represent a hydrogen atom or a substituent.
  • the bond of the C—C to C carbon chain may be a single bond or one of them may be a double bond.
  • a compound of the formula (XIV) characterized by subjecting a 2-hydroxy-1-N-aryl-1-acetamide derivative or a salt thereof obtained by the production method according to the above (37) to a hydrolysis reaction.
  • C-C-C represent a carbon chain which may have a substituent, and R 1 R 2 , R 2a and R 2b are the same or different and each represent a hydrogen atom or a substituent.
  • the bond of the carbon chain of CC to C may be a single bond or either one may be a double bond.
  • R 2 a, R 2 b, R 2 c and R 2 d is the same or different, a hydrogen atom or a substituent, R 3 is - 6 alkyl group indicates a] group represented by The process according to (6) above,
  • Z represents an optionally substituted methylene group
  • RR 2 , R 2a , R 2b , R 2 c and R 2 d are the same or different and each represents a hydrogen atom or a substituent, and R 3 represents a 16 alkyl group] or a salt thereof;
  • Z is a methylene group which may be substituted, R 1 R 2 , R 2a , R 2b , R 2c and R 2d are the same or different, and represent a hydrogen atom or a substituent; R 3 is a compound represented by (: shows a 6- alkyl group) or a salt thereof;
  • R 2 a, R 2 b, R 2 c and R 2 d is the same or different, a hydrogen atom or a substituent, R 3 represents a _ 6 alkyl group represented by A compound or a salt thereof;
  • Z is an optionally substituted methylene group, RR 2, R 2 a, R 2 b, R 2 c and R 2 d is the same or different, a hydrogen atom or a substituent, R 3 is C ⁇ - compounds represented by 6 an alkyl group] or a salt thereof;
  • Z is a methylene group which may be substituted, R 1 R 2 , R 2a , R 2b , R 2c and R 2d are the same or different, and represent a hydrogen atom or a substituent; R 3 is - compounds represented by 6 an alkyl group] or a salt thereof;
  • R 2 , R 2a , R 2b , R 2c and R 2d are the same or different and each represent a hydrogen atom or a substituent, and R 3 represents a 6- alkyl group] Or a compound thereof according to the above (42), which is subjected to a peroxide reaction. Is the method for producing Q salt;
  • R 2, R 2 a, R 2 b, R 2 c and R 2 d is the same or different, a hydrogen atom or a substituent
  • R 3 is - shows the 6 alkyl group represented by The compound or a salt thereof is subjected to an N-oxide reaction to obtain the compound or a salt thereof according to the above (42), and the compound or a salt thereof is converted to a compound of the formula (VIII)
  • Q represents a leaving group
  • Z represents an optionally substituted methylene group
  • R 1 represents a hydrogen atom or a substituent.
  • the compound or a salt thereof is subjected to a smile rearrangement reaction to obtain the compound or a salt thereof according to the above (41).
  • R 2 R 2 a, R 2 b, R 2 c and R 2 d is the same or different, a hydrogen atom or a substituent
  • R 3 is - shows the 6 alkyl group represented by Compound or salt thereof and formula (VIII)
  • the “basic hydroxyl compound” used in the reaction of the present invention includes a hydroxide of an alkali metal or an alkaline earth metal.
  • hydroxides of alkali metal include lithium hydroxide, sodium hydroxide, hydroxide hydroxide and the like; hydroxides of alkaline earth metal include magnesium hydroxide and calcium hydroxide, for example. Etc.
  • an alkali metal hydroxide is preferred, and among them, sodium hydroxide and hydroxide hydroxide are preferred, and sodium hydroxide is particularly preferred.
  • the “amide solvent” used in the reaction of the present invention includes a chain or cyclic amide solvent.
  • Chain amide solvents include, for example, N, N-dimethylformamide, N, N-dimethylacetamide; and "cyclic amide solvents” include, for example, 1-methyl-2-pyrrolidone, 1,3 —Dimethyl-2-imidazolidinone and the like.
  • amide solvent used in the reaction of the present invention, a “chain amide solvent” is preferable, and among them, N, N-dimethylformamide and N, N-dimethylacetamide are preferable, and in particular, N, N-dimethylacetamide is more preferred.
  • aromatic homo- or heterocyclic ring represented by ring A examples include, for example, benzene, naphthalene, anthracene, phenanthrene, pyrene, naphthacene, chrysene, triphenylene, indene, indane, tetrahydronaphthalene, 1,2-dihydronaphthalene, Aromatic rings having 6 to 18 carbon atoms (including those in which a non-aromatic hydrocarbon ring is fused to a phenyl group) such as 4-dihydronaphthalene and a steroid skeleton.
  • the steroid skeleton has the formula:
  • the rings I, J, K, and L constitute a tetracyclic fused hydrocarbon ring, and one or three of the rings I, J, and K are aromatic rings.
  • a ring that is not an aromatic ring may include a double bond in the bond forming the ring. ].
  • Aromade includes aromatic monocyclic heterocycles (eg, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole 1,3,4-thoxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2
  • aromatic or heterocyclic ring optionally having substituent (s) represented by ring A is preferably “aromatic homocyclic ring optionally having substituent (s)”.
  • the “aromatic homo- or heterocyclic ring” in the “optionally substituted aromatic homo- or heterocyclic ring” represented by the ring A may be a “condensed ring” as described above.
  • the “substituent” in the “optionally substituted aromatic homo- or heterocyclic ring” represented by ring A includes, for example, a lower (C 1 ⁇ ) alkyl group (eg, methyl, ethyl Le, propyl, isopropyl, heptyl, Isopuchinore, sec- heptyl, tert one heptyl, pentyl, isopentyl, neopentyl, hexyl, etc.), lower (C, - 6) alkenyl [e.g., Biel, Ariru (allyl), 1 one Propenyl, 2-meth 1-Propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl—2-
  • Aryl groups eg, phenyl, ⁇ -naphthyl, mononaphthyl, etc.
  • aromatic heterocyclic groups eg, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3- Oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3- Triazolyl, 1,2,4_triazolyl, tetrazolyl, pyridinole, pyridazinyl, pyrimigel, pyrazinyl, triadinole, benzofurael, isobenzofurinole, benzo [b] chenyl, indolin
  • N- disubstituted amino group e.g., Jimechiruamino, di Echiruamino, Jibuchirua 'Mino, Jiariru (allyl) Amino, N- methyl- such as N- Fueniruamino, alkyl, C 2 - 6
  • N- (alkyl) such as rubamoyl group, N-monosubstituted rubamoyl group [eg, methyl rubamoyl, ethylcarbamoyl, cyclohexynolecanolevamoyl, phenyl-rubamoyl] ) force Rubamoiru group, N- (C 2 - 6 alkenyl Honoré) force Rubamoiru group, N- (C 3 _ 7 cycloalkyl) force Rubamoiru group, N- (C 6 4.
  • rubamoyl group N-monosubstituted rubamoyl group [eg, methyl rubamoyl, ethylcarbamoyl, cyclohexynolecanolevamoyl, phenyl-rubamoyl] ) force Rubamoiru group, N- (C 2 - 6 alkenyl Honoré) force Rubamoiru group, N- (C 3
  • N N-disubstituted rubamoinole group [eg, dimethylcarbamoyl, getylcarbamoyl, dibutylcarbamoyl, diallylallylbamoyl, N-methyl-N-phenylca
  • Bamoiru alkyl group, C 2 _ 6 Aruke - le group, C 3 _ 7 cycloalkyl group and C 6 -, etc.
  • N-monosubstituted sulfamoyl group eg, N- ( 6- alkyl) sulfamoyl group such as methylsulfamoyl, ethylsulfamoyl, cyclohexylsulfamoyl, phenylsulfamoyl, N— (C 2 one 6 alkenyl) Surufamoi Le group, N- (C 3 - 7 cycloalkyl) sulfamoyl groups, N- (C 6 _ 1 0 7 reel) Surufamoi / Les group such], N, N-disubstituted sulfamoyl group [e.g. , Dimethyl snorefamoinole, getylsulfamoyl, dibutino
  • alkoxy-carboyl group eg, methoxycarbonyl, ethoxycanoleboninole, propoxycano Levoninole, isopropoxycarbonole, butoxycanoleboninole, isobutoxycanoleponinole, sec-butoxycanoleboninole, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycanoleponyl
  • oxo hydroxyl
  • lower (C ⁇ ) alkoxy group e.g., methoxy, ethoxy alkoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy sheets, tert- butoxy, Penchiruokishi to, etc.
  • Kishiruokishi a lower (C 2 "6) Alkenyloxy groups [eg, allyloxy, 2-butenyl Okishi, 2 - pentenyl old xylene, Kiseninore old alkoxy, etc.] to 3-, C 3 _ 7 Shikuroanoreki / Reokishi group (e.g., cyclopropyl O alkoxy, cyclobutyl O alkoxy, cyclopentyloxy Ruo alkoxy, the consequent opening Kishiruokishi, the consequent opening, etc. Puchiruokishi) , C 6 _ i. Ariruokishi group (e.g., phenoxy, etc.
  • Shikuroanoreki / Reokishi group e.g., cyclopropyl O alkoxy, cyclobutyl O alkoxy, cyclopentyloxy Ruo alkoxy, the consequent opening Kishiruokishi, the consequent opening, etc
  • Nafuchiruokishi C 7 - (- such as 4 Arukiruokishi group.
  • Ariru one C Bok 4 alkylthio group such as Nafuchiru C 1-4 alkyl Chio).
  • Ariruchio group e.g., phenylene thioether, etc. naphthylthio
  • lower (C Preparative 6) alkyl sulfide two Honoré group eg, Mechirusurufi two Honoré, E Chino less Honoré sulfinyl, propyl sulfinyl, I isopropyl sulfinyl, Buchirusurufi - Le , Isobutylsulfinyl, sec-butinoresolefininore, tert-butylinoresorefininore, pentinoresorerefinore, isopentinoresorerefinore, neopentinoresorerefinore, the like Kishinoresunorefu Iniru), C 7 - 14 ⁇ La
  • 6 _ i such ⁇ Li one Roux C i _ 4 alkylsulfonyl E Honoré group), C 6 _ 1Q ⁇ reel sulfonyl group (e.g., Hue - Le Sulfo - le, etc.
  • Nafuchirusu Ruhoniru a sulfo group, Shiano group, azide group, a halogen atom (e.g., fluorine, chlorine, bromine, iodine), a nitro group, a nitroso group, be esterified
  • phosphono group e.g., a phosphono group, (C Preparative 6 an alkoxy) phosphoryl group such as ethoxy phosphoryl, diethoxyphosphoryl and di (. Bok 6 alkoxy) phospho Lil groups such as Le]
  • phosphono group which may be Esuterui spoon in substituted lower (Cj. 6) alkyl group e.g., phosphono one Ci _ 6 alkyl group, 6 alkoxy phosphoryl
  • acyl group may form a 5- to 7-membered ring together with a part of the “aromatic homo- or heterocyclic ring”.
  • the “aromatic homo- or heterocycle j” represented by the ring A ′ is the “aromatic homo- or heterocycle optionally having a substituent” represented by the above-mentioned ring A. And heterocyclic ”.
  • Ring A is preferably “an aromatic homo- or heterocyclic ring which has an electron-withdrawing group and may further have a substituent”.
  • the electron-withdrawing group include an acyl group (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, pareryl, Valeri ⁇ ⁇ , Vivaloyl, Hexanoyl, Heptanoyl, Octanoyl, Cyclopropane, Pancarbonyl, Cyclobutanecanoleboninole, Cyclopentancanoleboninole, Sikh, Hexanecanoleponinole, Crotoninole, 2-cyclohexenolenolenole I le, such Nikochinoiru, C 2 _ 8 Arukanoiru group, C 3 _ 8 Arukenoiru group, C 3 _ 7 cycloalkyl - Karuponiru group, C 3 _ 7 Shikuroaruke two Lou carbon
  • Aryl-carbonyl group a heterocyclic ring formed by combining a 5- or 6-membered aromatic or non-aromatic heterocyclic ring having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom with a carbonyl group N- monosubstituted rubamoyl group [eg, N-—6-alkyl) such as methylcarbamoyl, ethylcarbamoyl, cyclohexylcarbamoyl, phenylcarbamoyl, etc. .
  • N- monosubstituted rubamoyl group eg, N-—6-alkyl
  • Sulphamoyl group N-monosubstituted sulphamoyl group [eg, methylsolefamoyl, ethylsulfamoinole, hexylsulfamoino] Les, such as Hue acylsulfamoyl N- ( ⁇ Bok 6 alkyl) sulfamoyl group, N- (C 2 - 6 alkenyl) sulfamoyl groups, N- (C 3 _ 7 cycloalkyl) sulfa carbamoyl group, N_ (Ce-i .
  • sulphamoyl group eg, methylsolefamoyl, ethylsulfamoinole, hexylsulfamoino
  • Les such as Hue acylsulfamoyl N- ( ⁇ Bok 6 alkyl) sulfamoyl group, N- (C 2 -
  • a carboxyl group eg, methoxycarbol, ethoxycarbonyl, propoxycarbol, Isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycanole bonore, tert-butoxycanolebonole, pentyloxyca Luponyl, hexyloxycarbonyl, etc.
  • the electron-withdrawing group is preferably an acryl group (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, norrelyl, isovaleryl, pivaloyl, hexanoyl, heptanyl, otatanyl, cyclopropanecarbonyl, cyclobutane canoleboninolene, cyclopentene, cyclopentene) Kanoreboninore, hexane force Lupo cyclohexane - Honoré, Kurotono I Le, 2-cyclopropyl hexene force Ruponiru, Benzoinore, C 2 _ 8 Arukanoiru groups such Nikochinoiru, C 3 8 Arukenoiru group, C 3 7 cycloalkyl one group , C 3 _ 7 cycloalkenylcarbonyl group, C 6 — i.
  • an acryl group eg, formyl,
  • acyl group may form a 5- to 7-membered ring together with ring A, for example of the formula:
  • X is one O—; one S—; _S (O)-; -S (O) 2 —; — P + R lx R 2x — (R lx and R 2x Represents a hydrogen atom or a substituent, respectively); and represents ⁇ — or NR 1 — (R 1 represents a hydrogen atom or a substituent).
  • R 1 represents a hydrogen atom or a substituent.
  • one O—; — S —; — S (O)-; -S (O) 2 — is preferable, and one O— is particularly preferable.
  • Y is one o_; — S—; _s (o) one; one s
  • R lxx R 2xx R 1 x and R 2 each represent a hydrogen atom or a substituent); _ ⁇ —; NR la — (R 1 a represents a hydrogen atom or a substituent) or One CR ⁇ 'R 2 ''— (R 1 ", R 2 " represents a hydrogen atom or a substituent). Among them, one NR 1 — (R 1 represents a hydrogen atom or a substituent) is preferable.
  • X is 10—; 1S—; _S (O) 1 or 1 S (O) 2 — (particularly 1— ), and Y is —NR 1 — (R 1 is hydrogen Represents an atom or a substituent).
  • Examples of the “ replacement group” represented by RR lx , R 2x , R lxx , R 2xx , R la , R 1 ′′ and R 2 ′′ include, for example, methyl, ethyl, allyl, cyclohexyl , d_ 6 alkyl group, such as phenyl, C 2 _ 6 alkenyl, C 3 - 7 cycloalkyl, Cs-i.
  • Aryl groups acyl groups (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, norrelinole, isovaleryl, pinocyloyl, hexanoyl, heptanol, octanoyl, cyclopropanecarbonyl, cyclobutanecarbol, cyclopentanecanolepoyl Nore, Hexane hex power / Repoegre, Krotnoinore, 2-si Black to Kisenkanorepo - Honoré, Benzoinore, C 2 such Nikochinoinore - 8 Anorekanoinore group, C 3 _ 8 Arukenoiru group, c 3 _ 7 cycloalkyl one carbonyl group, c 3 _ 7 cycloalkenyl chromatography carbonyl group, C 6 _ 1Q 7 A 5- or 6-membered aromatic or non-ar
  • I 1 , R lx , R 2x , R lxx , R 2xx , R la , R 1 ′′ and R 2 ′′ are preferably a hydrogen atom or an alkyl group.
  • B is an “aromatic or heterocyclic ring optionally having substituent (s)”
  • X and Y are the aromatic or heterocyclic ring. It shall be bonded to each of the above adjacent ring-constituting atoms.
  • Examples of the “substituent” in the “optionally substituted ethylene group” for B include, for example, the substitution in the “optionally substituted aromatic homo- or heterocyclic” for the ring A.
  • Examples of the group include those exemplified above.
  • the substituent is preferably an anolequinole group, a hydroxyl group, oxo, or the like.
  • B is preferably an optionally substituted ethylene group, particularly preferably an ethylene group having two _ 4 alkyl group and Okiso.
  • W represents an oxygen atom or a sulfur atom. You. Of these, an oxygen atom is preferred.
  • Aryl group acyl group (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, norrelinole, isovaleryl, vivalonole, hexanol, heptanoinole, octanol, cyclopropancanolebonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclopentanecarbonyl Kisankanorepo two Norre cyclohexane, black Tonoinore, 2- consequent opening to xenon Nkanorepo two Honoré, Benzoi / Les, C 2 _ 8 Anorekanoiru group, C 3 _ 8 ⁇ Rukenoiru groups such Nikochinoinore, C 3 - 7 cycloal
  • R 1 is particularly preferably a hydrogen atom.
  • the compounds represented by the formulas (III) and (IV) or salts thereof are each a compound represented by the formulas (I) and (II) wherein B is an optionally substituted ethylene group. Or its salt.
  • the bond of B bonded to X in the formula (I) also bonds to X in the formula (II) after the Smiles rearrangement reaction, and the bond of B bonded to Y in the formula (I). Also bonds to Y in equation ( ⁇ ) after the Smiles rearrangement reaction.
  • the elimination represented by Q is, for example, a halogen atom (eg, chlorine atom, bromine atom, iodine atom), a reactive residue of sulfonic acid (eg, meta And the like. Among these, a halogen atom is preferable, and a bromine atom is more preferable.
  • the above formulas (X), (XI), (XII) and (XIV) furthermore, the above formula:
  • C—C—C represents a carbon chain which may have a substituent.
  • substituents include the same substituents as those in the “aromatic homo or hetero ring optionally having substituent (s)” represented by ring A.
  • the bond of the C to C to C carbon chains may be a single bond or one of them may be a double bond.
  • R 2 , R 2a and R 2b are the same or different and represent a hydrogen atom or a substituent.
  • substituents include the same substituents as those in the "optionally substituted aromatic homo- or heterocyclic ring" represented by ring A.
  • R 2 , R 2a and R 2b are preferably a hydrogen atom.
  • R 2 , R 2a , R 2b , R 2e and R 2d are the same or different Represents a hydrogen atom or a substituent.
  • substituents include the same substituents as those in the “optionally substituted aromatic homo- or heterocyclic ring” represented by ring A.
  • R 2 , R 2a , R 2b , R 2c and R 2d are preferably hydrogen atoms.
  • the 6 alkyl group for example Mechinore, Echiru, propyl, iso Puropinore, Puchinore , Isoptinole, sec-butinole, tert-butyl, pentinole, Isopenpentole, neopentyl, hexinole, and the like. Of these, methyl is preferred.
  • the salt of the compound used in the present invention is not particularly limited, but a pharmaceutically acceptable salt is preferable, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, an organic acid And salts with basic or acidic amino acids.
  • a pharmaceutically acceptable salt is preferable, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, an organic acid And salts with basic or acidic amino acids.
  • the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt, ammonium salt and the like.
  • salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylene Salt with jamine etc. can be obtained.
  • salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Preferred examples of the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, conodic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, Salts with p-toluenesulfonic acid and the like can be mentioned.
  • Preferred examples of salts with basic amino acids include, for example, salts with arginine, lysine, or-tin
  • preferable examples of salts with acidic amino acids include, for example, aspartic acid, glutamic acid, and the like. Salts.
  • a compound represented by the formula (II) or a salt thereof (hereinafter, abbreviated as compound (I)) is subjected to a Smiles rearrangement reaction to give a compound represented by the formula (II).
  • Substituted aromatic compound or a salt thereof (hereinafter abbreviated as compound (II)) can be produced.
  • the Smiles rearrangement reaction is carried out, for example, by adding a basic hydroxide to a solution of compound (I) in an amide-based solvent and stirring the reaction solution.
  • the amount of the basic hydroxylated compound used in the Smiles rearrangement reaction is usually 1 to 50 mol, preferably 2 to 25 mol, per 1 mol of the modified compound (I).
  • the smiles The reaction temperature in the reaction is usually from 120 to 150 ° C, preferably from 0 to 75 ° C, particularly preferably from 15 to 50 ° C.
  • the reaction time in the smile reaction is usually 0.5 to 5 hours.
  • Compound (II) can be isolated and purified according to a method known per se.
  • the method for isolating compound ( ⁇ ) is based on the case where compound (II) is amorphous
  • the compound (II) is isolated by separating the reaction solution containing the compound (II) with water and an organic solvent and concentrating the organic phase. I can do it. Further, purification operations such as distillation may be performed as necessary.
  • the compound (II) when the compound (II) is a crystal, the compound (II) can be isolated by adding water to the reaction solution containing the compound (II) and collecting the precipitated crystal by filtration. Further, compound (II) can be isolated by the same operation as in the case where compound (II) is amorphous. Further, purification operations such as recrystallization may be performed as necessary. Alternatively, the reaction solution containing compound (II) may be directly used for the next reaction without isolating compound (II).
  • the compound represented by the formula (III) or a salt thereof is, for example, a compound represented by the formula (VII) or a salt thereof (hereinafter, referred to as a compound (III)).
  • Compound (VII)) and an alkylating agent of the formula (VIII) or a salt thereof hereinafter abbreviated as compound (VIII)).
  • any solvent may be used as long as it does not participate in the reaction with the reaction raw materials.
  • the solvent include, for example, hydrogenated hydrocarbons (eg, chloroform, dichloromethane, 1,2-dichloroethane, and tetrachloromethane).
  • Chlorinated hydrocarbons, etc. ethers (eg, diisopropy ether, getyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxetane, etc.), nitriles (eg, acetonitrile, propionitrile, etc.) And aromatic hydrocarbons (toluene, benzene, black benzene, etc.), alcohols (eg, methanol, ethanol, isopropanol, tert-butanol, etc.), and the above-mentioned “amide solvents”.
  • the medium may be used alone, in a mixture, or as an aqueous solution.
  • the solvent is preferably the amide solvent described above.
  • This reaction is preferably performed in the presence of a base.
  • a base examples include metal hydrides (eg, sodium hydride, etc.), metal alkoxides (eg, sodium methoxide, etc.), organic bases (eg, triethylamine, Diazabicycloundecene, etc.), alkali metal carbonates (eg, sodium carbonate, etc.), and the above-mentioned “basic hydroxides”. These bases may be used alone or as a mixture.
  • the base is preferably the above-mentioned “basic hydroxylated product”.
  • This reaction is particularly preferably carried out in the above-mentioned “amide-based solvent” in the presence of the above-mentioned “basic hydroxyl group”.
  • the amount of the base (preferably a basic hydroxylated compound) used in this reaction is generally 1 to 6 mol, preferably 1.5 to 4 mol, more preferably 2 to 1 mol of compound (VII).
  • the amount of compound (VIII) to be used is generally 1-6 mol, preferably 1.5-4 mol, more preferably 2-3 mol, per 1 mol of compound (VII).
  • the reaction temperature in this reaction is usually from 120 to 150 ° C, preferably from 0 to 50 ° C, particularly preferably from 15 to 30 ° C.
  • the reaction time in this reaction varies depending on the raw materials used, but is usually 1 to 24 hours.
  • the compound (III) thus obtained can be isolated and purified according to a method known per se, as in the case of the compound (II) described above.
  • reaction solution containing the compound (III) may be directly subjected to the next Smiles rearrangement reaction without isolating the compound (III).
  • Compound (VII) and compound (VIII) described above can be produced according to a method known per se.
  • the compound represented by formula (IV) or a salt thereof (hereinafter abbreviated as compound (IV)) contained in compound (II) is subjected to a hydrolysis reaction to give a compound represented by formula (IX). And a salt thereof (hereinafter, abbreviated as compound (IX)).
  • the hydrolysis reaction is performed, for example, by adding water to a solution of compound (IV) and then heating. If necessary, the basic hydroxyl
  • the hydrolysis reaction may be performed in the presence of a compound.
  • the reaction solution containing the compound (IV) may be used as it is, or the isolated compound (IV) May be used in the above “amide solvent”.
  • the reaction temperature in the hydrolysis reaction is usually 100 to 150 ° C.
  • the reaction time in the hydrolysis reaction is usually 0.5 to 5 hours.
  • the compound (IX) thus obtained can be isolated and purified according to a method known per se, in the same manner as in the above-mentioned compound (II).
  • the compound (IX) thus obtained has high purity.
  • “Production of compound (III) by reacting compound (VII) with compound (VIII)” "Production of compound (IV) by subjecting compound (III) to a Smiles rearrangement reaction” and " Production of compound (IX) by subjecting (IV) to hydrolysis reaction”
  • the compound (IX) can be obtained consistently with high yield from compound (VII).
  • the compound represented by the formula (XII) or a salt thereof hereinafter, abbreviated as compound (XII)
  • Compound (X) can be isolated from the reaction mixture according to a conventional method that can be used in the next reaction as a reaction mixture or as a ⁇ -product, and recrystallized. It can also be easily purified by ordinary separation means such as
  • Compound (XI) can be used in the next reaction as a reaction mixture or as a compound, but can also be isolated from the reaction mixture according to a conventional method, and can be easily separated by ordinary separation means such as recrystallization. It can also be purified.
  • compound (XIV) a compound represented by formula (XIV) or a salt thereof (hereinafter, abbreviated as compound (XIV)) can be produced.
  • This reaction is carried out in the same manner as in the above-mentioned hydrolysis reaction of compound (IV). Specifically, this reaction is carried out by adding water to a reaction mixture containing the compound (XI), followed by heating. In the present hydrolysis reaction, if necessary, a basic hydroxide such as sodium hydroxide may be added.
  • the compound (XV) can be produced, for example, by subjecting a compound represented by the formula (XVI) or a salt thereof (hereinafter abbreviated as compound (XVI)) to a Smiles rearrangement reaction. This reaction is carried out in the same manner as in the above-mentioned Smiles rearrangement reaction of compound (I).
  • the compound (XV) thus obtained can be isolated and purified according to a method known per se.
  • the compound (XVI) can be produced, for example, by reacting a compound represented by the formula (XVII) or a salt thereof (hereinafter abbreviated as compound (XVII)) with compound (VIII).
  • the compound (XVI) thus obtained may be used as a reaction mixture or as a compound in the next reaction, or may be isolated and purified according to a method known per se.
  • the compound (XVII) can be produced, for example, by subjecting a compound represented by the formula (XVIII) or a salt thereof (hereinafter abbreviated as compound (XVIII)) to a peroxide reaction. This reaction can be carried out according to an acid reaction known per se.
  • the compound (XVII) thus obtained may be used in the next reaction as a reaction mixture or as a product, or may be isolated and purified according to a method known per se.
  • the above compound (XVIII) can be produced according to a method known per se.
  • Compound (XVI) can also be produced, for example, by subjecting a compound represented by the formula (XIX) or a salt thereof (hereinafter abbreviated as compound (XIX)) to an N-oxidation reaction. it can. This reaction can be carried out according to a known acid reaction.
  • the compound (XVI) thus obtained may be used in the next reaction as a reaction mixture or as a crude product, or may be isolated and purified according to a method known per se.
  • the compound (XIX) can be produced, for example, by reacting a compound represented by the formula (XVIII) or a salt thereof (hereinafter abbreviated as compound (XVIII)) with compound (VIII).
  • Compound (XV) can also be produced, for example, by subjecting a compound represented by the formula (XX) or a salt thereof (hereinafter abbreviated as compound (XX)) to an N-oxidation reaction. This reaction can be carried out according to a known acid reaction.
  • Compound (XX) can be produced by subjecting compound (XIX) to a Smiles rearrangement reaction.
  • XIV compound (XV), etc.) are useful, for example, as a raw material for producing a compound or a salt thereof used for treating or preventing a metabolic disease.
  • the compound (XIV) obtained by the production method of the present invention is also useful as a raw material for, for example, a melayun-concentrating hormone antagonist described in WO01 / NO21577.
  • those compounds in which R 3 is methyl can be obtained, for example, by subjecting the methyl to the desired substitution according to the method described in JP-A-63-201167 or a method analogous thereto. After introducing a group and subjecting it to a hydrolysis reaction similar to the hydrolysis reaction of the compound (IV), it can be used as a raw material for an antiarrhythmic drug described in JP-A-63-201167.
  • the present invention will be described in more detail with reference to Test Examples, Examples, and Reference Examples. 1 The present invention is not limited to these.
  • room temperature means a temperature of 1 ° C to 30 ° C.
  • Example 5 487 mg (3 mmo 1) of 6-hydroxy-1-tetralone was dissolved in 4.5 mL of dimethinoreacetamide. 36 Omg (9 mmo 1) of sodium hydroxide was added, and the mixture was stirred at room temperature for 1 hour. 2-Promo 2-methylpropanamide 1.494 g (9 mmo 1) was added, and the mixture was stirred for 5 hours. 1.080 g (27 mmol) of sodium hydroxide was added, and the mixture was stirred at 50 ° C for 1 hour. 4.5 mL of water was added, and the mixture was refluxed for 1 hour. 9 mL of water and seed crystals were added to the reaction solution, and the mixture was gradually cooled to room temperature. The precipitated crystals were collected by filtration and washed three times with 4.5 mL of water. The crystals were dried under reduced pressure to obtain 287 mg of 6-amino-1-tetralone as white crystals.
  • Example 6 487 mg (3 mmo 1) of 6-hydroxy-1-te
  • the precipitated crystals are collected by filtration, washed three times with 2raL of water, dried under reduced pressure, and dried at a reduced pressure to give 2-hydroxy-2-methyl-N- (2-methyl-1-oxoxide-6-quinolinyl) pupanamide 141 ⁇ 2g (55.4% yield) as pale yellow crystals.
  • the Smiles rearrangement reaction is carried out under mild conditions, even in a compound unstable to heat, the atoms bonded to the aromatic ring can be removed using a safe reagent. Can be easily replaced.
  • a generally available phenol derivative is used as a raw material, an inexpensive, safe and toxic resin reagent is used, and a one-pot, high-purity aniline derivative is obtained in a high yield. Can be manufactured.
  • a 6-amino-1-tetralone derivative can be easily synthesized by using a 6-hydroxy_1-tetralone derivative as a raw material and only passing through two novel intermediates for production.
  • 6-aminoquina / resin is carried out in one pot by using a 6-hydroxyquinaldine derivative as a raw material and via a novel production intermediate. N-oxide derivatives can be easily synthesized.

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Abstract

L'invention concerne un procédé de préparation de composés aromatique substitués de formule générale (I) ou de sels desdits composés. Dans cette formule, A est un homocycle ou un hétérocycle aromatique éventuellement substitué, X est -O- ou analogue, Y est NR1- ou analogue, et B est un homocycle ou un hétérocycle aromatique éventuellement substitué ou un éthylène éventuellement substitué. Ce procédé consiste à soumettre les composés de formule générale (I) ou les sels desdits composés à un réarrangement de Smiles, chaque symbole étant tel que défini ci-dessus. On opère le réarrangement de Smiles en présence d'un hydroxyde basique dans un solvant amidique. Ledit procédé permet de résoudre les problèmes liés au réarrangement de Smiles. On peut ainsi préparer efficacement une pluralité de composés aromatiques par réarrangement de Smiles, lesdits composés pouvant être utilisés comme médicaments, produits chimiques agricoles ou produits intermédiaires destinés à la production de produits chimiques à usages divers.
PCT/JP2001/009422 2000-10-27 2001-10-26 Procede de preparation de composes aromatiques substitues et produits intermediaires associes WO2002034712A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2343280A1 (fr) * 2009-12-10 2011-07-13 Bayer CropScience AG Dérivés de quinoléine fongicides
US8188117B2 (en) 2005-07-26 2012-05-29 Sanofi-Aventis Piperidinyl-substituted isoquinolone derivatives
US8278294B2 (en) 2006-12-27 2012-10-02 Sanofi Substituted isoquinoline and isoquinolinone derivatives as inhibitors of Rho-kinase
US8399482B2 (en) 2008-06-24 2013-03-19 Sanofi 6-substituted isoquinolines and isoquinolinones
US8501736B2 (en) 2005-06-28 2013-08-06 Sanofi Isoquinoline derivatives
US8524737B2 (en) 2008-06-24 2013-09-03 Sanofi Bi- and polycyclic substituted isoquinoline and isoquinolinone derivatives
US8541449B2 (en) 2008-06-24 2013-09-24 Sanofi Substituted isoquinolines and isoquinolinones as Rho kinase inhibitors
US8609691B2 (en) 2005-07-26 2013-12-17 Sanofi Cyclohexylamin isoquinolone derivatives
US8710077B2 (en) 2006-12-27 2014-04-29 Sanofi Cycloalkylamine substituted isoquinoline and isoquinolinone derivatives
US8710228B2 (en) 2006-12-27 2014-04-29 Sanofi Cycloalkylamine substituted isoquinoline derivatives
US8742116B2 (en) 2006-12-27 2014-06-03 Sanofi Cycloalkylamine substituted isoquinolone derivatives
US8748614B2 (en) 2006-12-27 2014-06-10 Sanofi Substituted isoquinoline and isoquinolinone derivatives
US8772492B2 (en) 2006-12-27 2014-07-08 Sanofi Substituted isoquinoline and isoquinolinone derivatives
CN106631843A (zh) * 2016-11-23 2017-05-10 山东友帮生化科技有限公司 一种3‑氧代环丁基氨的制备方法

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WO1988009328A1 (fr) * 1987-05-22 1988-12-01 Bracco Industria Chimica S.P.A. Preparation de derives de 5-acylamino-2,4,6-triiodo- ou tribromo-acide benzoique

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WO1988009328A1 (fr) * 1987-05-22 1988-12-01 Bracco Industria Chimica S.P.A. Preparation de derives de 5-acylamino-2,4,6-triiodo- ou tribromo-acide benzoique

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8501736B2 (en) 2005-06-28 2013-08-06 Sanofi Isoquinoline derivatives
US8722671B2 (en) 2005-06-28 2014-05-13 Sanofi Isoquinoline derivatives
US8188117B2 (en) 2005-07-26 2012-05-29 Sanofi-Aventis Piperidinyl-substituted isoquinolone derivatives
US8796458B2 (en) 2005-07-26 2014-08-05 Sanofi Cyclohexylamine isoquinolone derivatives
US8609691B2 (en) 2005-07-26 2013-12-17 Sanofi Cyclohexylamin isoquinolone derivatives
US8461144B2 (en) 2006-12-27 2013-06-11 Sanofi Substituted isoquinoline and isoquinolinone derivatives
US8710077B2 (en) 2006-12-27 2014-04-29 Sanofi Cycloalkylamine substituted isoquinoline and isoquinolinone derivatives
US8710228B2 (en) 2006-12-27 2014-04-29 Sanofi Cycloalkylamine substituted isoquinoline derivatives
US8742116B2 (en) 2006-12-27 2014-06-03 Sanofi Cycloalkylamine substituted isoquinolone derivatives
US8748614B2 (en) 2006-12-27 2014-06-10 Sanofi Substituted isoquinoline and isoquinolinone derivatives
US8772492B2 (en) 2006-12-27 2014-07-08 Sanofi Substituted isoquinoline and isoquinolinone derivatives
US8278294B2 (en) 2006-12-27 2012-10-02 Sanofi Substituted isoquinoline and isoquinolinone derivatives as inhibitors of Rho-kinase
US8524737B2 (en) 2008-06-24 2013-09-03 Sanofi Bi- and polycyclic substituted isoquinoline and isoquinolinone derivatives
US8541449B2 (en) 2008-06-24 2013-09-24 Sanofi Substituted isoquinolines and isoquinolinones as Rho kinase inhibitors
US8399482B2 (en) 2008-06-24 2013-03-19 Sanofi 6-substituted isoquinolines and isoquinolinones
EP2343280A1 (fr) * 2009-12-10 2011-07-13 Bayer CropScience AG Dérivés de quinoléine fongicides
CN106631843A (zh) * 2016-11-23 2017-05-10 山东友帮生化科技有限公司 一种3‑氧代环丁基氨的制备方法

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