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WO2008010578A1 - Procédé de fabrication d'un dérivé du styrène - Google Patents

Procédé de fabrication d'un dérivé du styrène Download PDF

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Publication number
WO2008010578A1
WO2008010578A1 PCT/JP2007/064364 JP2007064364W WO2008010578A1 WO 2008010578 A1 WO2008010578 A1 WO 2008010578A1 JP 2007064364 W JP2007064364 W JP 2007064364W WO 2008010578 A1 WO2008010578 A1 WO 2008010578A1
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general formula
chemical
reaction
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compound represented
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Japanese (ja)
Inventor
Shin-Itsu Kuwabe
Hideo Masaoka
Karl-Heinz Giselbrecht
Johann Hiebl
Klaus Reiter
Wolfgang Skranc
Andre Hendrikus Maria De Vries
Johannes Gerardus De Vries
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Ono Pharmaceutical Co Ltd
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Ono Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms

Definitions

  • the present invention relates to a method for producing a styrene derivative useful as a synthetic intermediate for various pharmaceuticals, and a novel styrene derivative.
  • Styrene derivatives are generally useful compounds as pharmaceutical intermediates.
  • Styrene derivatives are generally useful compounds as pharmaceutical intermediates.
  • Styrene derivatives are generally useful compounds as pharmaceutical intermediates.
  • a method for producing a styrene derivative a method in which a butyl chloride derivative and an organozinc reagent are subjected to a coupling reaction in the presence of a nickel catalyst (for example, see Non-Patent Document 1) is disclosed.
  • Patent Document 1 Pamphlet of International Publication No. 05/103017
  • Non-patent literature 1 Bulletin 'Ob ⁇ The ⁇ Academy ⁇ Ob ⁇ Sciences' Ob ⁇ The You SSR 'Division' of the Chemicals Science, Volume 35, No. 3, pp. 620-622, 1986
  • An object of the present invention is to develop a production method that can obtain a styrene derivative useful as a synthetic intermediate of various pharmaceuticals easily and in high yield. More specifically, the present invention relates to a production method capable of efficiently obtaining 5- (3-ethoxy-3-oxopropyl) 7,8-dihydronaphthalene 1-inorebivalate (Compound B).
  • the present inventors have found that the above-mentioned general formula is obtained in a non-aqueous solvent in the presence of a catalytic amount of a phosphine complex of nickel or palladium, particularly a phosphine complex of nickel.
  • a styrene derivative represented by the above general formula (III), particularly 5- (3-ethoxy-3-oxopropyl) is produced by a coupling reaction of the compound represented by the general formula ( ⁇ ) with the compound represented by the formula (I).
  • a method for efficiently obtaining 7,8-dihydronaphthalene-1-yl bivalate (compound B) was found.
  • the present invention provides:
  • R 2 and R 3 each independently represent a hydrogen atom or C ;! to 4 alkyl group, and R 1 and R 2 may be joined together to form C;!
  • R 4 Represents a Cl to 4 alkynole group, C;!
  • m represents an integer of 0 or 1 to 3, and when m is 2 or more, a plurality of R 4 may be the same or different It also has two R 4 May be substituted with adjacent carbon atoms to form a saturated monocyclic group together with the carbon atoms to which they are bonded
  • R 5 represents an optionally protected hydroxyl group
  • X 1 Represents a chlorine atom or a trifluoromethanesulfoxyloxy group.
  • step (3) (4) subjecting the product of step (3) to an esterification reaction in the presence of an acid catalyst in an organic solvent;
  • step (4) The product of step (4) is converted into 2- [5 methyl-2- (4 methylphenyl) 1,3 oxazoluluyl 4-ethyl] ethyl 4-methylbenzenesulfonate, inorganic acid salt and organic phase transfer catalyst. Subjecting to etherification reaction in a solvent suspension;
  • step (6) A step of subjecting the product obtained in step (5) to a hydrolysis reaction in a water-containing solvent in the presence of an alkali metal hydroxide,
  • C;! To 4 alkyl groups include, for example, linear or branched C such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec butyl, and tert butyl groups; -4 alkyl groups and the like.
  • C;! to 6 alkyl groups include, for example, linear or branched groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec butyl, tert butyl, pentyl, hexyl groups and the like. Examples thereof include a branched Cl-6 alkyl group.
  • examples of C;!-4 alkylene groups include methylene, ethylene, propylene, butylene groups and the like.
  • C;! To 4 alkoxy group includes, for example, linear or branched Cl such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec butoxy, tert butoxy group, etc. -4 alkoxy groups and the like.
  • examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the saturated monocyclic group formed together with the carbon atom to which they are bonded is, for example, a saturated monocyclic
  • a saturated monocyclic examples thereof include a carbocycle or a saturated monocyclic heterocycle.
  • Saturated monocyclic carbocycles include C3-8 saturated monocyclic carbocycles, and specific examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like.
  • Saturated monocyclic heterocycles include:!
  • the “protecting” group in the “optionally protected hydroxyl group” is not particularly limited as long as it does not participate in the reaction.
  • a nickel phosphine complex is a compound in which nickel and a phosphine ligand are coordinated to form a complex, and is usually a catalyst used in a chemical reaction. If it is, it will not specifically limit.
  • a catalyst used in a chemical reaction If it is, it will not specifically limit.
  • NiCl dibromobis (triphenylphosphine) nickel (NiBr (PPh)), di
  • 1,3-bis (diphenylphosphino) propane nickel chloride power S can be mentioned.
  • nickel compounds for example, nickel chloride (11), nickel acetate (11), bis (acetylacetone) nickel (Ni (acac))), bis (1, 5-Cyclootatagene) Nickel (Ni (COD)), Bis (1, 10—
  • the phosphine complex of noradium is a compound in which noradium and a phosphine ligand are coordinated to form a complex, and is usually a catalyst used for a chemical reaction. If it is, it will not be specifically limited.
  • a catalyst used for a chemical reaction If it is, it will not be specifically limited.
  • Phenylphosphinophene dichloropalladium (PdCl (dppf)), phenylbisiodide (
  • a palladium compound for example, palladium acetate ( ⁇ ), palladium carbon, palladium black, dichlorodiallyl palladium (PdCl 2 (al
  • examples of the phosphine ligand include R— or S—2, 2′-bis (diphenylphosphino) -1,1,1′-binaphthyl (R—, S—BINAP), bis (2-diphenylphosphinophenore) ether (DPEphos), 1,3-bis (diphenylphosphino) pronylphosphino) phenocene (dppf), tri-tert-butylphosphine (t-Bu P), Tolish
  • Methyl hexylphosphine (PCy) and the like, and complexes not exemplified above are those
  • the catalytic amount of the above-mentioned Lucerne or palladium phosphine complex is about 0.01 mol% to equivalent (100 mol% to 100 mol% of the compound represented by the general formula (I)). 1 00 mole 0/0) force s, and more preferably from about 0.1 mole 0/0 to about 10 mole 0/0.
  • nickel The catalytic amount of 1,3-bis (diphenylphosphino) propane nickel chloride is about 2 mol% to about 10 mol with respect to 100 mol% of the compound represented by the general formula (I). About 3 mol% is preferred, with mol% being preferred.
  • examples of the inert gas include nitrogen gas, argon gas and the like, and any of them is preferable.
  • the non-aqueous solvent means a solvent that does not release protons, and is not particularly limited as long as it does not participate in the reaction.
  • ether solvents for example, tetrahydrofuran, dioxane, jetyl.
  • Ether isopropyl ether, methyl tert-butylene ethere, dimethoxyethane, diethyleneglyconoresimethylenoateolene, cyclopentyl methyl ether, etc.), ketone solvents (eg acetone, methyl ethyl ketone, 2-butanone, N-methyl) —2-pyrrolidone, etc.), nitrile solvents (eg, acetonitrile, propionitrile, etc.), amide solvents (eg, N, N-dimethylacetamide, N, N-dimethylformamide, etc.), aromatic hydrocarbons Solvent (for example, benzene, toluene, xylene, etc.), carbonate-based solvent (E.g., ethylene carbonate, Jefferies chill carbonate, dimethylcarbamoyl Honoré carbonate, propylene carbonate, methylate Honoré ethyl Honoré carbonate, butylene car Boneto etc
  • the water-containing solvent means a solvent containing water
  • the solvent is a solvent miscible with water, and is not particularly limited as long as it does not participate in the reaction.
  • Alcohol solvents for example, methanol, ethanol, propanol, isopropanol, etc.
  • the aforementioned ketone solvents, the aforementioned ether solvents, the aforementioned amide solvents and the like can be mentioned.
  • Alcohol solvents such as methanol, ethanol, propanol and isopropanol are preferred. If necessary, these solvents can be used in a mixture of two or more at an appropriate ratio.
  • the organic solvent is not particularly limited as long as it does not participate in the reaction.
  • Solvent, nitrile solvent, aliphatic hydrocarbon solvent examples thereof include a medium (for example, n-pentane, n-hexane, n-heptane, cyclohexane, dichloroethane, dichloromethane, etc.), the above-described aromatic hydrocarbon solvent, and the like.
  • Acetonitrile, N, N-dimethylformamide, acetone, tetrahydrofuran, dioxane, toluene and the like are preferable. These solvents may be used as a mixture of two or more at an appropriate ratio as necessary.
  • examples of the alkali metal hydroxide include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
  • examples of the acid catalyst include formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.
  • methane sulphonic acid is used.
  • examples of the inorganic acid salt include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, and the like.
  • it is a phosphate, and examples thereof include sodium phosphate, potassium phosphate, calcium phosphate, and magnesium phosphate.
  • examples of the phase transfer catalyst include tetraptyl ammonium bromide, tetraethyl ammonium bromide, tetraptyl ammonium chloride, triethylbenzyl chloride ammonium chloride, trimethyl ammonium chloride, and chloride chloride.
  • examples include trimethyldecyl ammonium, hexadecyl tributylphosphonium bromide, methyl tricapryl ammonium chloride, tetrabutyl ammonium hydrogen sulfate, and tetramethyl ammonium chloride.
  • Preferable examples include tetraethylammonium bromide.
  • R 1 and R 2 together are preferably C;! To 4 alkylene groups, more preferably R 1 and R 2 together are ethylene groups. .
  • a methyl group is preferred as R 4 .
  • R 5 is more preferably a hydroxyl group protected with a bivaloyl group, or a hydroxyl group protected with a bivaloyl group, preferably a hydroxyl group protected with a acetyl group.
  • R 5 ′ is more preferably a hydroxyl group, a hydroxyl group protected with a bivaloyl group, or a hydroxyl group preferably a hydroxyl group protected with a acetyl group.
  • X 1 may further represent a bromine atom or an iodine atom.
  • X 1 is preferably a chlorine atom!
  • M may further represent a boron atom, a titanium atom, a tungsten atom, or a magnesium atom.
  • M is preferably a zinc atom.
  • a hydroxyl group protected with a Cl-4 alkyl group is preferred, and a hydroxyl group protected with an ethyl group is more preferred! /.
  • M is preferably 0! /.
  • n is preferably an integer from!
  • the compound represented by the general formula (I) is preferably, for example, the general formula (I-1).
  • compound C 5-chloro-7,8-dihydronaphthalene 1-inolevevilate
  • the compound represented by the general formula ( ⁇ ) is preferably, for example, the general formula (I 1-1)
  • the compound represented by the general formula (III) is preferably a compound represented by the general formula (III 1).
  • the compound represented by the general formula (IV) is preferably, for example, 5-hydroxy-1-tetralone.
  • the compound represented by the general formula (A) is preferably, for example, 3- (5
  • the production method of the present invention will be described below. Specifically, the production method of the present invention is shown in the following steps.
  • the starting compound may be used as a salt.
  • a pharmaceutically acceptable salt can be used.
  • the pharmacologically acceptable salt is preferably non-toxic and water-soluble.
  • Suitable salts include, for example, salts of alkali metals (potassium, sodium, lithium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts (tetramethylammonium salt, tetrabutylammonium salt).
  • organic amines triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine, N-methyl-D darcamamine, etc.
  • Salts acid adduct salts (inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), organic acid salts (acetate, trifluoroacetic acid) Salt, lactate, tartrate, oxalate, fumarate, maleate, benzoate Salt, Kuen salt, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, Darukon salt etc.) etc.) are exemplified up. [0036] The symbols used for the compounds in the following steps represent the same meaning as described above unless otherwise specified.
  • the above step 1 is a chlorination reaction or a trifluoromethanesulfonyloxylation reaction.
  • the chlorination reaction is performed by using a compound represented by the general formula (IV) as a catalyst (for example, iron (III) chloride, In the presence of zinc (II) chloride) in an organic solvent (eg, n pentane, n hexane, n heptane, cyclohexane, dichloroethane, dichloromethane, etc.) or without solvent, with an organic acid (eg, acetic acid, trifluoroacetic acid, etc.) , Methanesulfonic acid, p-toluenesulfonic acid, etc.) in the presence or absence of carboxylic acid chloride (for example, bivaloyl chloride, acetyl chloride, etc.) at room temperature to 80 ° C.
  • carboxylic acid chloride for example, bivaloyl chloride,
  • R 5 in the general formula (I) is protected by ⁇ shea le groups in the carboxylic acid chloride used in the chlorination reaction It may be a hydroxyl group.
  • the trifluoromethanesulfonyloxylation reaction is carried out by converting the compound represented by the general formula (IV) into a base (for example, 2,6-di-tert-butylpyridine, diisopropylethylamine, triethylamine, dimethylaniline, sodium carbonate, etc.)
  • a trifluoromethane sulfonating agent for example, trifluoromethanesulfonic acid anhydride, trifluoromethanesulfuryl chloride, trifluoromethanesulfonyl bromide, etc.
  • an organic solvent for example, n-pentane) N hexane, n-heptane, cyclohexane, dichloroethane, dichloromethane, ethyl acetate, cetyl carbonate, etc.
  • step 1 is preferably a chlorination reaction.
  • the compound represented by the general formula (I) is converted into a nickel phosphine complex (for example, 1 Kel / 1,3-bis (difurphosphino) propane) or a palladium phosphine complex (for example, in the presence of a catalytic amount of bis (2-diphenylphosphinophenyl) ether, palladium acetate, etc.) in a non-aqueous solvent (eg, tetrahydrofuran, toluene, acetonitrile, etc.) at room temperature to 100 ° C, the general formula ( ⁇ ).
  • a non-aqueous solvent eg, tetrahydrofuran, toluene, acetonitrile, etc.
  • the compound represented by the general formula ( ⁇ ) is preferably used in a molar ratio of about 1.0 to 1.5 times, and 1.4 times the amount of the compound represented by the general formula (I). Is more preferable.
  • the reaction temperature is more preferably about 60 ° C, preferably room temperature to about 85 ° C.
  • the reaction time is particularly preferably about 1 hour to about 24 hours, preferably about 6 hours to about 24 hours, more preferably about 20 hours.
  • Step 2 the reaction treatment is performed, for example, with a non-aqueous solvent (for example, n-heptane, tetrahydrofuran, toluene, acetonitrile, etc.) and a highly polar solvent (for example, polyethylene glycol (for example) PEG) (for example, PEG400, etc.), and the high polarity solvent can be extracted with an organic solvent (for example, n-heptane, etc.).
  • a non-aqueous solvent for example, n-heptane, tetrahydrofuran, toluene, acetonitrile, etc.
  • a highly polar solvent for example, polyethylene glycol (for example) PEG) (for example, PEG400, etc.
  • phosphine complex of nickel in Step 2
  • 1,3-bis (diphenylphosphino) propane nickel chloride 1,3-bis (diphenylphosphino) propane nickel chloride
  • the reaction from the above step 1 to the step 2 is represented by the general formula (I) This is useful because it can be carried out continuously in one pot without separation.
  • Step 1 chlorination reaction using bivaloyl chloride, and then in Step 2, the compound represented by the general formula ( ⁇ -1) and 1,3-bis (diphenylphosphino) propane nickel chloride
  • Step 2 the compound represented by the general formula ( ⁇ -1) and 1,3-bis (diphenylphosphino) propane nickel chloride
  • the compound represented by the general formula (III) is a styrene derivative, particularly the following formula (B):
  • M a represents one Sn (R a ) B (R a ) or one B (OH) (in the group, R a represents C;!
  • the compound represented by the general formula (II) can be produced by the following step 4. However, if the compound represented by the general formula ( ⁇ - / 3) is a low-reactivity compound that is known to those skilled in the art, a halogen exchange reaction is performed to convert the compound into a high-reactivity compound. Can also be used.
  • X 3 represents a chlorine atom, a bromine atom, or an iodine atom, but represents an atom different from X 2, and other symbols have the same meaning as described above.
  • Step 3 is a halogen exchange reaction performed as desired.
  • a compound represented by the general formula ( ⁇ ) is converted into an alkali metal halide (for example, lithium chloride, lithium bromide, lithium iodide, chloride).
  • an alkali metal halide for example, lithium chloride, lithium bromide, lithium iodide, chloride.
  • an organic solvent eg, acetonitrile, ⁇ , ⁇ ⁇ ⁇ ⁇ dimethylformamide, acetone, tetrahydrofuran, etc.
  • this reaction may be performed under pressure.
  • step 4 the compound represented by the general formula (II / 3) is converted into an organic solvent (for example, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, methyl t-butyl ether, dimethoxyethane, diethylene glyconoresin methacrylate).
  • an organic solvent for example, tetrahydrofuran, dioxane, jetyl ether, isopropyl ether, methyl t-butyl ether, dimethoxyethane, diethylene glyconoresin methacrylate.
  • a metal for example, zinc, copper, tin, etc.
  • a catalyst for example, trimethylsilyl chloride, copper salts such as copper bromide, iodine, etc.
  • the compound represented by the general formula () -a) is composed of (1) a compound represented by the general formula ( ⁇ and an organic magnesium compound (for example, jetyl ether, tetrahydrofuran, etc.) (for example, , Methyl magnesium promide, ethyl magnesium promide, etc.) at 78 ° C., and then in an organic solvent (eg, jetyl ether, tetrahydrofuran, etc.), an alkyl tin compound (eg, hexamethylditine, hexane It can be produced by reacting with butylditin, trimethyltin bromide, tributyltin chloride, etc.
  • an organic magnesium compound for example, jetyl ether, tetrahydrofuran, etc.
  • an organic solvent eg, jetyl ether, tetrahydrofuran, etc.
  • an alkyl tin compound eg, hexamethylditine, he
  • Step 5 is a hydrolysis reaction, and the compound represented by the general formula (III) is converted to an alkali gold In the presence of a genus hydroxide (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), a water-containing solvent (eg, alcohol solvent (eg, methanol, ethanol, propanol, isopropanol, etc.)) and water In a mixed solvent) at 0 ° C to 80 ° C.
  • a genus hydroxide eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.
  • a water-containing solvent eg, alcohol solvent (eg, methanol, ethanol, propanol, isopropanol, etc.)
  • water In a mixed solvent 0 ° C to 80 ° C.
  • W 1 represents a protected hydroxyl group (for example, C; hydroxyl group protected with 4 to 4 alkyl groups, etc.) during the process.)
  • Step 6 is an esterification reaction.
  • a compound represented by the general formula (V) is converted into an acid catalyst (for example, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid). , Phosphoric acid, etc.) in the presence of an alcohol solvent (for example, methanol, ethanol, propanol, isopropanol, etc.) at 0 ° C to 80 ° C.
  • an acid catalyst for example, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid.
  • Phosphoric acid, etc. in the presence of an alcohol solvent (for example, methanol, ethanol, propanol, isopropanol, etc.) at 0
  • a method using an acid halide includes, for example, a compound represented by the general formula (V) in an organic solvent (such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran, etc.) or in an insoluble solvent.
  • an organic solvent such as chloroform, dichloromethane, jetyl ether, tetrahydrofuran, etc.
  • Reacting agents such as oxalyl chloride, thioyl chloride and the like at ⁇ 20 ° C to reflux temperature, the resulting acid halide is a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine).
  • Etc. in the presence of alcohol (eg, methanol, ethanol, propanol, isopropanol, etc.) and an organic solvent (chloroform, dichloromethane, jetyl ether, tetrahydrofuran, etc.) at a temperature of 0 ° C. to 40 ° C. Is done.
  • organic solvents dioxane, tetrahydrofuran
  • acid halide can be reacted at 0 ° C to 40 ° C.
  • a method using a mixed acid anhydride is, for example, a method in which a compound represented by the general formula (V) is used in an organic solvent (such as black mouth form, dichloromethane, jetyl ether, tetrahydrofuran) or without a solvent.
  • an organic solvent such as black mouth form, dichloromethane, jetyl ether, tetrahydrofuran
  • a method using a condensing agent includes, for example, a compound represented by the general formula (V) and an alcohol (for example, methanol, ethanol, propanol, isopropanol, etc.) and an organic solvent (chloroform, dichloromethane, dimethylformamide).
  • an alcohol for example, methanol, ethanol, propanol, isopropanol, etc.
  • organic solvent chloroform, dichloromethane, dimethylformamide
  • Step 7 is an etherification of a compound represented by the general formula (VI) with 2- [5 methyl-2- (4-methylphenyl) -1,3-oxazol-4-yl] ethyl 4 methylbenzenesulfonate Reaction, inorganic acid salt (eg, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate (eg, sodium phosphate, potassium phosphate, calcium phosphate, magnesium phosphate, etc.), Nitrates) and phase transfer catalysts (eg, tetrabutylammonium bromide, tetraethylammonium bromide, tetraptylammonium chloride, triethylbenzylammonium chloride, trimethylammonium chloride, trimethyldecyl chloride) Ammonium, hexadecyltributylphosphonium bromide, methyltricapryl ammonium chloride, t
  • this etherification reaction is carried out by using an alkali metal hydroxide (water) in an organic solvent (such as dimethylformamide, dimethyl sulphoxide, black mouth form, dichloromethane, jetyl ether, tetrahydrofuran, methylol butyl ether, etc.).
  • an organic solvent such as dimethylformamide, dimethyl sulphoxide, black mouth form, dichloromethane, jetyl ether, tetrahydrofuran, methylol butyl ether, etc.
  • Y represents an alkali metal.
  • the above step 8 is a hydrolysis reaction and is carried out by the same method as in the above step 5 using the compound represented by the general formula (VII).
  • examples of the alkali metal represented by Y include lithium, sodium, and potassium.
  • Step 8 the compound represented by the general formula (VII) can be continuously carried out in one pot without isolation. To that end, it is obtained in step 7.
  • Step 8 is performed while the compound represented by the general formula (VII) is suspended in an organic solvent (eg, dichloromethane, jetyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc.).
  • an organic solvent eg, dichloromethane, jetyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc.
  • the treatment means converting the alkali metal salt of carboxylic acid to carboxylic acid.
  • Each reaction step in the present specification is preferably performed under an inert gas (argon gas, nitrogen gas, etc.) atmosphere under anhydrous conditions.
  • an inert gas argon gas, nitrogen gas, etc.
  • each reaction product obtained is subjected to usual purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer. It can be purified by methods such as chromatography, column chromatography, ion exchange resin, scavenger resin or washing, recrystallization. Purification may be performed for each reaction or after completion of several reactions.
  • purification means for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer. It can be purified by methods such as chromatography, column chromatography, ion exchange resin, scavenger resin or washing, recrystallization. Purification may be performed for each reaction or after completion of several reactions.
  • each compound used as a starting material or a reagent is known per se, or a method described in the Examples below or a known method such as "Comprehensive Organic Transformations: A Guide to Functional Group”. Preparations, 2 edition (Richard C. Larock, John Wiley & Sons Inc, 1999) ”can be easily manufactured.
  • step 2 among the compounds represented by the general formula (I), compounds in which X 1 is a bromine atom, particularly 5- Bromo-7,8-dihydronaphthalene 1-il Vivalate (hereinafter abbreviated as Compound D) is used as a raw material compound to produce Compound B by a coupling reaction using a radium compound (International Publication) (Described in Production Example 9 of pamphlet No. 05/103017) had the following problems.
  • X 1 is a bromine atom, particularly 5- Bromo-7,8-dihydronaphthalene 1-il Vivalate
  • Compound D 5- Bromo-7,8-dihydronaphthalene 1-il Vivalate
  • a compound in which X 1 represents a chlorine atom, particularly 5-chloro-7,8-dihydronaphthalene-1 By using a nitrophenolate (compound C) as a raw material compound, a coupling reaction using a nickenole or palladium phosphine complex is carried out, thereby avoiding the use of an odor in steps 1 to 2 described above, and the compound It became possible to perform C continuously in one pot without isolation.
  • compound C is very stable even at high temperatures and its purity is constant, it is a production method that is not easily affected by impurities. Therefore, the production method of the present invention can be carried out by a simple and safe operation as compared with the conventional method described above, and the yield is increased, so that it is suitable for industrial production of Compound B.
  • Example 10 (1) any of the following examples may be used to obtain compound B. However, according to Example 8 and Example 9 (1) ⁇ Example 10 (1) It is preferable to manufacture. Furthermore, in order to obtain Compound A, any of the following examples may be used! /, But Example 8 and Example 9 (1) ⁇ Example 10 (1) ⁇ Example 1 1 ( 1) ⁇ Example 12 (1) ⁇ Example 13 (1) ⁇ Example 14 (1) ⁇ Example 15 It is preferable to manufacture according to Example 15.
  • the production method of the present invention is safe and suitable for industrial production, and as a styrene derivative useful as a synthetic intermediate for various target pharmaceuticals, a compound represented by the general formula (ii), particularly 5 — (3-Ethoxy-1-3-propyl) -1,7-8-dihydronaphthalene 1-ylpi A large amount of balates can be synthesized efficiently.
  • the chromatographic separation site and the solvent in Katsuko shown in the TLC indicate the elution solvent or developing solvent used, and the ratio indicates the volume ratio.
  • NMR is a measured value of 1 H NMR, and the solvent in the box shown at the NMR site indicates the solvent used for the measurement.
  • the compound name used in this specification is generally a computer program for naming according to the rules of IUPAC, the power using ACD Name (registered trademark, manufactured by Advanced Chemistry Development In), or Named according to the IUP AC nomenclature.
  • the obtained oil was cooled to a 5% aqueous methylamine solution (465 g). ), And extracted with 400 mU.
  • the aqueous layer was acidified with 6 mol / L hydrochloric acid (136 mU and extracted with ethyl acetate (300 mL and 200 mL). After washing with water (250 mL), concentrate and have the following physical properties To give the title compound (184 g).
  • the obtained compound was Yore, in the next reaction without further purification.
  • Example 2 Methyl 3-[(4 methylbenzoyl) amino] -4 oxopentanoate
  • acetic anhydride 250 mU, glacial acetic acid (15 mU and 4-dimethylaminopyridine (1.9 g)
  • pyridine 265 mL
  • acetic acid Ethyl 530 mU solution
  • Acetic acid was added to the reaction solution.
  • Example 6 5 oxo 5, 6, 7, 8 tetrahydronaphthalene 1-yl vivalate 5 hydroxy-1-tetralone (160 g) and triethylamine (151 mU in tetrahydrofuran (960 mU suspension, chlorinated in argon gas atmosphere) Bivaloyl (130 ⁇ 8 g) was added dropwise, and the mixture was stirred at room temperature for 3 hr.Water (480 mL) was added to the reaction solution, and extracted with tert butyl methyl ether (1280 mU.
  • the compound produced in Example 7 can also be produced by the following method.
  • the compound produced in Example 9 can also be produced by the following method.
  • Example 9 In a mixture of zinc powder (10.5 g), tetrahydrofuran (120 mU and trimethylsilyl chloride (1.20 mU) under an argon gas atmosphere, the compound (18. Og) prepared in Example 9 was placed in a chamber. The solution was added dropwise while paying attention to the rise in internal temperature. The mixture was stirred at room temperature for 20 hours to prepare an organozinc reagent.
  • Example 8 In a mixture of the compound prepared in Example 8 (15.9 g) and 1,3 bis (diphenylphosphino) propane nickel chloride (1.68 g) under an argon gas atmosphere, the prepared organic zinc reagent was added at room temperature. In addition, after heating to 55 ° C, the mixture was stirred for 16 hours. After cooling the reaction solution to room temperature, toluene (240 mU and ammonium chloride aqueous solution (214. 8 g) was added, the organic layer was separated, and the solvent was distilled off under reduced pressure. The resulting residue was diluted with n-heptane (120 mU). Dissolved, insolubles were removed by filtration, and washed with n-heptane (60 mU. The obtained filtrate was concentrated to obtain the title compound (20.9 g) having the following physical property values.
  • Example 10 The compound produced in Example 10 can also be produced by the following method.
  • Example 10 (1) (3-Ethoxy 3-oxopropyl) 7,8-dihydronaphthalene 1-inore pinoleate
  • Example 8 Under a nitrogen gas atmosphere, the compound prepared in Example 8 (224. 5 g) and 1,3 bis (diphenylphosphino) propane nickel chloride (6.6 g) were added. Then, while stirring at room temperature, 1400 mL of the prepared organozinc reagent solution (zinc reagent 1.26 mo) was added, and then the reaction solution was heated to 60 ° C. and stirred for 24 hours. The reaction solution was concentrated at 50 ° C. and the solvent was distilled off. Then, 10% acetic acid (500 mL) was added to the residue at 45 ° C., and the mixture was stirred for 1 hour for phase separation.
  • the prepared organozinc reagent solution (zinc reagent 1.26 mo) was added, and then the reaction solution was heated to 60 ° C. and stirred for 24 hours. The reaction solution was concentrated at 50 ° C. and the solvent was distilled off. Then, 10% acetic acid (500 mL) was added to the residue at 45 ° C.,
  • N-Heptane 300 mL was added to the aqueous layer, and the target product was extracted into the organic layer.
  • the organic layer obtained by phase separation after addition of 10% acetic acid was dissolved in polyethylene glycol (PEG) 400 (200 mL) and then extracted twice with n-heptane (first 1000 mL, second 500 mL). ).
  • PEG polyethylene glycol
  • Gain The combined n-heptane layers were combined, washed with water (l OOmU, and filtered using Tonsyl (trade name) (15 g).
  • Tonsyl trade name
  • Example 10 A mixture of the compound prepared in Example 10 or Example 10 (1) (20.8 g), ethanol (20 ⁇ 8 g) and 20% aqueous sodium hydroxide (43.2 g) was brought to 50 ° C under an argon gas atmosphere. Heat and stir for 1 hour. After cooling to room temperature, potassium hydrogen carbonate (24. Og), concentrated hydrochloric acid (10.6 g) and toluene (31.2 g) were added to the reaction mixture, insolubles were removed by filtration, and the phases were separated. The obtained aqueous layer was washed with toluene (20.8 g), heated to 45 ° C., and 20% aqueous sodium hydrogen sulfate solution (108.
  • Example 11 The compound produced in 1 can also be produced by the following method.
  • the compound (224 g) produced in Example 10 or Example 10 (1) was mixed with methanol ( 224 g), and a 20% aqueous sodium hydroxide solution (383 g) was further added at about 30 ° C. to 40 ° C. Subsequently, the reaction solution was heated at 70 ° C.
  • methanesulfonic acid (0.121 g) was added at room temperature to a solution of the compound prepared in Example 11 (9.17 g) in methanol (46.0 g), and then the reaction solution was brought to 40 ° C. Heat and stir for 5 hours. Potassium bicarbonate (0.42 g) and activated carbon (0.46 g) were added and the mixture was stirred at 30 ° C. for 10 minutes. After filtration, the residue was dissolved in methanol (5. OmU, and the solvent was distilled off under reduced pressure. Toluene 1 ⁇ 24.4 g) was heated to 60 ° C, and 6.7% potassium bicarbonate was added. An aqueous solution (13.8 g) was added. The organic layer was separated and washed with water (9.2 g), and the solvent was distilled off under reduced pressure. Recrystallization was performed using toluene to obtain the title compound (9. Og) having the following physical property values.
  • Example 12 The compound produced in Example 12 can also be produced by the following method.
  • Example 11 (1) Under a nitrogen gas atmosphere, the compound (32 g) produced in Example 11 (1) was heated and dissolved in a methanol (129 g) solution. Azeotropic dehydration was performed at 60 ° C, and anhydrous methanol was added. After the dehydration was completed, the mixed solution was cooled to 40 ° C. Methanesulfonic acid (0.72 g) was added and stirred for 4 hours. After cooling to room temperature, add a solution of tripotassium phosphate (0.9 g) in water (15 mU) The pH was adjusted to 7.1. The reaction solvent was distilled off at 60 ° C under reduced pressure, toluene (150 g) was added, and methanol was further distilled off azeotropically.
  • a methanol 129 g
  • Azeotropic dehydration was performed at 60 ° C, and anhydrous methanol was added. After the dehydration was completed, the mixed solution was cooled to 40 ° C. Methanes
  • the obtained toluene solution was washed with water (2 ⁇ 30 mL) at 60 ° C.
  • Activated carbon (1.2 g) was added to the organic layer and stirred at 70 ° C for 1 hour, followed by filtration.
  • the obtained filtrate was concentrated to about 100 g at 70 ° C., and then the solution was cooled to about 20 ° C.
  • the precipitated crystals were collected by filtration, washed with toluene (50 g), and dried under reduced pressure at 50 ° C. to 60 ° C. to obtain the title compound having the same physical property values as described in Example 12 (26. 3g).
  • Example 5 The compound prepared in Example 5 (15.06 g) was suspended in a suspension of tripotassium phosphate (12.06 g) and tetraethylammonium bromide (0.60 g) in toluene (41.25 g) under an argon gas atmosphere. 82 g) and a solution prepared by dissolving the compound (8.25 g) prepared in Example 12 with toluene (49.5 g) by heating was added at 70 ° C. After the reaction mixture was stirred for 16 hours, tetra-ethylene ammonium bromide (0.60 g) was added, and the mixture was further stirred at 70 ° C. for 48 hours. The reaction mixture was cooled to 40 ° C.
  • Example 13 The compound produced in Example 13 can also be produced by the following method.
  • Example 5 In a suspension of tripotassium phosphate (21.4 g) and tetraethylammonium bromide (0 ⁇ 94 g) in water (0.86 g) and toluene (143 g) under a nitrogen gas atmosphere. The compound prepared in (22.8 g) and the compound prepared in Example 12 (1) (13.0 g) were added, and the suspension was heated to 70 ° C. and stirred for 20 hours. The reaction solution was cooled to 40 ° C., water (104 mL) was added, and the mixture was stirred for 30 minutes, and then phase separation was performed. The organic layer was washed at 40 ° C.
  • Example 14 3— (5— ⁇ 2 -— [5 Methyl-2- (4 methylphenyl) 1, 3 oxazo 1-ru 4-inore] ethoxy ⁇ 3,4-dihydronaphthalene 1-inore) propanoic acid sodium salt
  • Example 14 The compound produced in Example 14 can also be produced by the following method.
  • Example 13 To a toluene solution of the compound (24 g) produced in (1) (toluene 24 g, total amount 48 g) was added isopropanol (48 g) and heated to 55 ° C, and then 20% aqueous sodium hydroxide solution (14.5 g ) was added and stirred for 4 hours.
  • the obtained precipitate was washed with toluene (24 g) and dried overnight at 40 ° C. under reduced pressure to obtain the title compound (21.6 g) having the following physical property values.
  • Example 15 3— (5— ⁇ 2— [5 Methyl-2- (4 methylphenyl) 1, 3 oxazo 1ru 4 yl] ethoxy ⁇ —3, 4-dihydronaphthalene-1 yl) propanoic acid (Compound A )
  • Example 14 In an argon gas atmosphere, a mixed solution of the compound (8.06 g) prepared in Example 14 or Example 14 (1) in water (56.2 g) and ethanol (15. lg) was heated to 45 ° C. 2 mol / L hydrochloric acid (10.3 mU was added. To the resulting suspension was heated water (75.6 g) heated to 50 ° C., 30 minutes at 45 ° C., then 2 ° C. at 25 ° C. The obtained crystals were collected, washed with water, and dried to give the title compound (7.15 g) having the following physical data as a white solid.
  • the production method of the present invention is useful because a styrene derivative that can be used as an intermediate for various drugs can be easily obtained in a high yield. Furthermore, the styrene derivative obtained by the production method of the present invention, for example, the styrene derivative represented by the general formula (III), is useful as an intermediate of a compound having peroxisome proliferator-activated receptor agonist activity.

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Abstract

L'invention concerne un procédé de fabrication d'un dérivé du styrène représenté par la formule générale (III), en particulier le pivalate de 5-(3-éthoxy-3-oxopropyl)-7,8-dihydronaphtalène-1-yle avec efficacité; ledit procédé comprenant l'opération consistant à conduire une réaction de couplage d'un composé représenté par la formule générale (I) avec un composé représenté par la formule générale (II) dans un solvant non aqueux en présence d'une quantité catalytique d'un complexe de phosphine de nickel ou de palladium, en particulier d'un complexe de phosphine de nickel. Le dérivé de styrène est utile comme intermédiaire pour la synthèse de divers agents pharmaceutiques. Dans les formules (I), (II) et (III) chaque symbole est tel que défini dans la description.
PCT/JP2007/064364 2006-07-21 2007-07-20 Procédé de fabrication d'un dérivé du styrène Ceased WO2008010578A1 (fr)

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JP2019513702A (ja) * 2016-11-01 2019-05-30 エルジー・ケム・リミテッド エステル系組成物の製造方法

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JP2001261585A (ja) * 2000-03-15 2001-09-26 Chemiprokasei Kaisha Ltd ハロゲン化ビニル化合物の合成法
WO2005103017A1 (fr) * 2004-04-20 2005-11-03 Ono Pharmaceutical Co., Ltd. Procédé d’augmentation de la surface spécifique d’un médicament légèrement soluble

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JP2001261585A (ja) * 2000-03-15 2001-09-26 Chemiprokasei Kaisha Ltd ハロゲン化ビニル化合物の合成法
WO2005103017A1 (fr) * 2004-04-20 2005-11-03 Ono Pharmaceutical Co., Ltd. Procédé d’augmentation de la surface spécifique d’un médicament légèrement soluble

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JP2019513702A (ja) * 2016-11-01 2019-05-30 エルジー・ケム・リミテッド エステル系組成物の製造方法
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