WO2003101944A1 - Procede de production d'un compose ayant un groupe biphenyle auquel est substitue un groupe alkylthio inferieur - Google Patents

Procede de production d'un compose ayant un groupe biphenyle auquel est substitue un groupe alkylthio inferieur Download PDF

Info

Publication number
WO2003101944A1
WO2003101944A1 PCT/JP2003/006659 JP0306659W WO03101944A1 WO 2003101944 A1 WO2003101944 A1 WO 2003101944A1 JP 0306659 W JP0306659 W JP 0306659W WO 03101944 A1 WO03101944 A1 WO 03101944A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
water
added
reaction
mixture
Prior art date
Application number
PCT/JP2003/006659
Other languages
English (en)
Japanese (ja)
Inventor
Akira Okuyama
Yoshiyuki Masui
Yoji Kitaura
Original Assignee
Shionogi & Co., 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 Shionogi & Co., Ltd. filed Critical Shionogi & Co., Ltd.
Priority to AU2003241826A priority Critical patent/AU2003241826A1/en
Publication of WO2003101944A1 publication Critical patent/WO2003101944A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane

Definitions

  • the present invention relates to a simple and economical method for producing a compound having a biphenyl group substituted with a lower alkylthio group.
  • Matrix metaoral protease is an enzyme that contains zinc in the enzyme and degrades extracellular matrix (collagen, gelatin, fibronectin, etc.) as a substrate. This enzyme is thought to be involved in various pathologies such as osteoarthritis, tumor metastasis or invasion, congestive heart failure, nephritis, and retinopathy.
  • Patent Documents 1 and 2 and Non-Patent Documents 1 to 3 have excellent activity.
  • Non-Patent Document 2 reports the following two methods for synthesizing a sulfonamide derivative having a biphenyl group.
  • Patent Document 3 Patent Document 3
  • Patent Document 4 Patent Document 4
  • Patent Document 5 (Patent Document 5)
  • Non-Patent Document 1 Japanese Patent Application Laid-Open No. Hei 8—1 4 3 5 3 4 (Non-Patent Document 1)
  • Non-Patent Document 3 (Non-Patent Document 3)
  • X 2 is a halogen, a salt thereof or a solvate thereof is subjected to an alkylthioation reaction, wherein the compound is represented by the following general formula (IV):
  • R 1 is lower alkyl which may be substituted
  • a salt thereof or a solvate thereof.
  • R 1 has the same meaning as 1), a salt thereof, or a solvate thereof, which is subjected to a halogenation reaction, wherein the compound represented by the general formula (II):
  • X 1 is a halogen), a salt thereof, or a solvate thereof.
  • R 1 has the same meaning as 1); X 1 has the same meaning as 2)), a salt thereof, or a solvate thereof, and a general formula (III): H 2 N or 2 (-I )
  • R 2 is lower alkyl which may be substituted, aryl which may be substituted, aralkyl which may be substituted, heteroaryl which may be substituted, or heteroarylalkyl which may be substituted.
  • alkyl halides, dialkyl carbonates, alkyl sulfinates, alkyl sulfonates, dialkyl sulfates, alkyl esters, alkyl phosphites, nitrates, acetates, and tetras The method according to any one of 1) to 4), wherein an alkylating agent selected from the group consisting of alkylammonium salts is added.
  • an alkylating agent selected from the group consisting of alkyl halides, dialkyl carbonates, alkyl sulfinates, alkyl sulfonates, dialkyl sulfates, and tetraalkylammonium salts is preferable.
  • an alkylating agent selected from the group consisting of alkyl halides, dialkyl carbonates, alkyl sulfonates, and dialkyl sulfates and tetraalkylammonium salts is preferred.
  • R 2 has the same meaning as 3), a salt thereof, or a solvate thereof, which is subjected to an amidation reaction, wherein the compound represented by the general formula (I):
  • R 1 has the same meaning as 1), a salt thereof, or a solvate thereof, which is subjected to a halogenation reaction, wherein the compound represented by the general formula (II):
  • R 1 has the same meaning as 1; X 1 has the same meaning as 2)
  • a salt thereof or a solvate thereof.
  • R 1 has the same meaning as 1
  • a salt thereof, or a solvate thereof Particularly, a compound wherein R 1 is methyl, a salt thereof, or a solvate thereof is preferred.
  • This compound is an important intermediate in the synthesis of pharmaceuticals containing biphenylsulfonamide.
  • R 1 has the same meaning as 1
  • X 1 has the same meaning as 2
  • R 1 has the same meaning as 1
  • X 1 has the same meaning as 2
  • R 1 has the same meaning as 1
  • X 1 is not chlorine
  • a salt thereof or a solvent thereof.
  • Japanese foods are also new.
  • a compound in which R 1 is methyl, a salt thereof, or a solvate thereof is preferable.
  • compounds wherein X 1 is chlorine, salts thereof, or solvates thereof.
  • This compound is an important intermediate for synthesizing pharmaceuticals containing biphenylsulfonamide.
  • X 2 is a halogen, a salt thereof or a solvate thereof is subjected to an alkylthioation reaction, wherein the compound is represented by the following general formula (IV):
  • R 3 and: 3 ′ are simultaneously a hydrogen atom or a lower alkyl, or a ring containing R 3 and R 3 ′ together containing an adjacent oxygen atom. Or a salt thereof, or a solvate thereof, and a compound represented by the general formula (VII):
  • R 11 is a compound represented by the formula: or a salt thereof, or a solvate thereof.
  • R 2 is hydrogen, optionally substituted lower alkyl (substituent is hydroxy, lower alkyloxy, lower alkylthio, carboxy, or carbamoyl), benzyl, or indole-3-ylmethyl The production method according to any one of 3) to 13).
  • R 2 is hydrogen, methyl, isopropyl, Lee Sopuchiru, sec- heptyl, Cal Pamoirumechiru force Rubamoiruechiru, 2 Mechiruchioechiru, human Dorokishimechi Le, carboxymethyl, Karubokishechiru, phenyl, benzyl or Lee down de, 14.
  • halogen means fluorine, chlorine, bromine, and iodine.
  • chlorine and bromine are used.
  • halogen for X 2 , chlorine or bromine is preferred. In particular, bromine is preferred.
  • ⁇ lower alkyl '' used alone or in combination with other terms includes a linear or branched monovalent hydrocarbon group having 1 to 8 carbon atoms.
  • a C1-C6 alkyl is mentioned. Even more preferred are C 1 -C 3 alkyl.
  • methyl, ethyl, n-propyl, isopropyl, n-butyl, isoptyl, sec-butyl, tert-butyl and the like are preferable. Further, methyl and ethyl are preferred. Methyl is most preferred.
  • methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl, sec-butyl, tert-butyl and the like are preferable.
  • Methyl, ethyl, isopropyl, isoptyl, sec-butyl are even more preferred.
  • R 3 and R 3 ′ methyl, ethyl, n-propyl, isopropyl and the like are preferable. Further, methyl is preferred.
  • methyl ethyl and the like are preferable. Further, methyl is preferred.
  • aryl used alone or in combination with other terms includes a simple or condensed cyclic aromatic hydrocarbon.
  • phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like can be mentioned.
  • Phenyl as "Ariru” in R 2, 1 - naphthyl, 2-naphthyl, etc. Is mentioned. Phenyl is preferred.
  • the “aralkyl” is the above “lower alkyl” substituted by one or more “aryl”, and these may be substituted at all possible positions.
  • benzyl eg, 2-phenylethyl
  • phenylpropyl eg, 3-phenylpropyl
  • naphthylmethyl eg, 1-naphthylmethyl, 2-naphthylmethyl
  • anthrylmethyl eg, 9-anthrylmethyl, etc.
  • aralkyl for R 2, benzyl, phenylethyl, naphthylmethyl and the like are preferable. Further, benzyl is preferred.
  • the term ⁇ heteroaryl j '' used alone or in combination with other terms is an arbitrarily selected 5 to 6 containing one or more oxygen, sulfur or nitrogen atoms in the ring.
  • Pyrrolyl for example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl
  • furyl for example, 2-furyl, 3-furyl
  • chenyl for example, 2- phenyl, 3-
  • Chenyl imidazolyl (eg, 2-imidazolyl, 4-imidazolyl)
  • pyrazolyl eg, 1-pyrazolyl, 3-virazolyl
  • isothiazolyl eg, 3-isothiazolyl
  • isokiki Zolyl eg, 3-isoxazolyl
  • oxazolyl eg, 2-oxazolyl
  • thiazolyl eg, 2-thiazolyl
  • pyridyl eg, 2-pyridyl, 3-pyridyl, 4-pyridyl
  • virazinyl for example, 2-pyrazinyl
  • pyrimidinyl eg, 2-pyrimidinyl, 4-pyrimidinyl
  • heteroarylalkyl refers to a “lower alkyl” wherein one or two or more of the above “heteroaryl” are substituted at any position of the “lower alkyl”, and these are substituted at all possible positions. sell.
  • thiazolylmethyl for example, 4-triazolylmethyl
  • thiazolylethyl for example, 5-thiazolyl-2-ethyl
  • benzothiazolylmethyl for example, (benzothiazol-2-yl) methyl
  • indolylmethyl Eg, (indole-3-yl) methyl
  • imidazolylmethyl eg, 4-imidazolylmethyl
  • benzothiazolylmethyl eg, 2-benzothiazolylmethyl
  • indazolylmethyl for example, 1-indazolylmethyl
  • benzotriazolylmethyl for example, 1-benzotriazolylmethyl
  • benzoquinolylmethyl for example, 2-benzoquinolylmethyl
  • Benzoymidazolylmethyl for example, 2-benzylazomidazolylmethyl
  • pyridylmethyl for example, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl
  • pyridylmethyl for example,
  • halo lower alkyl used alone or in combination with other terms refers to the aforementioned “lower alkyl” substituted at 1 to 8, preferably 1 to 5 positions by the “halogen”. "Is included. For example, trifluoromethyl, trichloromethyl, difluoroethyl, trifluoroethyl, dichloroethyl, trichloroethyl and the like can be mentioned. Preferable is trifluoromethyl.
  • examples of the substituent in the “optionally substituted lower alkyl” include cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), hydroxy, lower alkyloxy (eg, methoxy) , Ethoxy, t-butoxy), mercapto, lower alkylthio (eg, methylthio, ethylthio), halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, t-yl) Butoxycarbonyl), halo-lower alkyl, halo-lower alkyloxy (eg, trifluoromethyloxy), amino optionally substituted with lower alkyl (eg, amino, methylamino, dimethylamino, ethylamino, getylamino) , Methylethylamino
  • substituent for the “optionally substituted lower alkyl” for R 2 preferred are a hydroxy group, a lower alkyloxy group, a lower alkylthio group, a carboxyl group and a carpamoyl group.
  • Substituents in “optionally substituted aryl”, “optionally substituted heteroaryl”, “optionally substituted aralkyl”, and “optionally substituted heteroarylalkyl” include: Optionally substituted lower alkyl, cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), lower alkenyl (eg, vinyl, propenyl, butenyl), lower alkynyl (ethynyl, propynyl), Droxy, lower alkyloxy (for example, methoxy, ethoxy, t-butoxy), mercapto, lower alkylthio (for example, methylthio, ethylthio), halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl (for example, , Methoxyl Nil, ethoxycarbonyl, t-butoxycarbonyl), halo-lower al
  • R 1 SH for example, methyl mercaptan gas (methane thiol)
  • KSR 1 is generated.
  • alkylating agent means a reagent used for a reaction for introducing an alkyl group into an organic compound.
  • examples include alkyl halides, dialkyl carbonates, alkyl sulfinates, alkyl sulfonates, dialkyl sulfates, alkyl phosphates, alkyl phosphites, nitrates, acetates, and tetraalkyl ammonium salts.
  • alkyl nodogenides include methyl iodide, methyl bromide, methyl chloride, chloroiodide, chlorobromide, chlorochloride, propyl iodide, propyl bromide, propyl chloride, isopropyl iodide, and bromide.
  • Dialkyl carbonate includes dimethyl carbonate, getyl carbonate, dipropyl carbonate, and diisocarbonate Propyl, dibutyl carbonate, di-S-butyl carbonate, t-butyl carbonate and the like.
  • alkyl sulfinate examples include methyl sulfinate, ethyl sulfinate, propyl sulfinate, isopropyl sulfinate, butyl sulfinate and the like.
  • alkyl sulfonate examples include alkyl triflate (methyl triflate, ethyl triflate, propyl triflate, isopropyl triflate, butytriflate, etc.), alkyl tosylate (methyl tosylate, ethyl tosylate) , Propyl tosylate, isopropyl tosylate, butyl tosylate, etc.), alkyl mesylate (methyl mesylate, ethyl mesylate, propyl mesylate, isopropyl mesylate, butyl mesylate, etc.), alkyl brosylate (methyl prosylate, ethyl brosylate, etc.
  • dialkyl sulfate examples include dimethyl sulfate, getyl sulfate, dipropyl sulfate, diisopropyl sulphate, dibutyl sulphate, s-butyl sulphate and t-butyl sulphate.
  • alkyl phosphates include trialkyl phosphate (such as trimethyl phosphate and triethyl phosphate), dialkyl phosphate (such as dimethyl phosphate and getyl phosphate), and phosphoric acid.
  • Monoalkyl monomethyl phosphate, monoethyl phosphate, etc.).
  • alkyl phosphite examples include trialkyl phosphite (trimethyl phosphite, triethyl phosphite, etc.), dialkyl phosphite (dimethyl phosphite, getyl phosphite, etc.) ), Monoalkyl phosphite (monomethyl phosphite, monoethyl phosphite, etc.).
  • nitrate include trifluoromethyl nitrate.
  • acetate examples include trifluoromethyl acetate.
  • the tetraalkylammonium salts include phenyltrimethylammonium chloride, phenyltrimethylammonium bromide, phenyltrimethylammonium iodide, and phenyltrimethylammonium iodide. And the like.
  • alkyl halide dialkyl carbonate, alkyl sulfonate (alkyl tosylate, alkyl mesylate, etc.), dialkyl sulfate, tetraalkyl ammonium salt and the like.
  • Particularly preferred are methyl iodide, methyl bromide, chloro iodide, dimethyl bromobromide, dimethyl carbonate, ethyl methyl tosylate carbonate, ethyl tosylate, methyl mesylate, dimethyl ethyl mesylate sulfate, dimethyl sulphate sulfate, and methylammonium chloride. Is mentioned.
  • the term "catalyst” is used in a chemical reaction system in a relatively small amount to change the reaction rate, start the reaction, or select a reaction without changing the result. Means a compound which is allowed to proceed. Examples include palladium compounds, rhodium compounds, platinum compounds, copper compounds, and ruthenium compounds. Palladium compounds are preferred.
  • the ring represented by “R 3 and R 3 ′ may be combined with each other to form a ring containing an adjacent oxygen atom” includes the following ⁇ .
  • the compound is not limited to a particular isomer but includes all possible isomers (eg, optical isomers) and racemates. Further, a pharmaceutically acceptable salt or a solvate thereof is also included.
  • a pharmaceutically acceptable salt or a solvate thereof is also included.
  • an alkali metal lithium, sodium, potassium, cesium, etc.
  • an alkaline earth metal magnesium, calcium, norium, etc.
  • ammonium etc.
  • Salts with organic bases and amino acids, or inorganic acids hydroochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.
  • organic acids acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid.
  • solvate of the compound used in the present invention includes, for example, solvates with organic solvents, hydrates and the like. When forming a hydrate, it may be coordinated with any number of water molecules.
  • This step is a step of sulfonating a biphenyl halogen derivative (X) as a starting material.
  • compound (V) can be obtained.
  • a solvent such as chloroform, dichloromethane, hexane, heptane, and toluene, or a mixed solvent thereof.
  • 1 to 10 equivalents, preferably 1.5 to 5 equivalents of the sulfonating agent is added to compound (X).
  • the usual post-treatment is performed.
  • compound (V) can be obtained.
  • Examples of the sulfonating agent include sulfuric acid, fuming sulfuric acid, and black sulfuric acid. Black sulfuric acid is preferred.
  • the salt examples include a lithium salt, a sodium salt, a potassium salt, a cesium salt, an ammonium salt and the like. Potassium salts are preferred.
  • Compound (V) is dissolved in a solvent such as water, methanol or ethanol, and a base is added.
  • the reaction mixture is allowed to react at 0 ° C to 100 ° C, preferably 5 ° C to 50 ° C, for 0.5 hours to 24 hours, preferably for 0.5 hours to 5 hours.
  • the compound (V a) can be obtained by performing the following post-treatment.
  • a salt (Va) of a biphenyl halogen derivative as a starting material is alkylthioated to obtain a compound (IVa).
  • the alkylthioation reaction mainly includes the third step, but the second step, the third step, the third step, the fourth step, the second step, the third step ">> the fourth step, and the compound The step of directly synthesizing compound (IV) from (V) is also included.
  • the compound (IVa) can be obtained by reacting for 5 to 20 hours, preferably for 3 hours to 10 hours, and performing a usual post-treatment.
  • a lithium salt, a sodium salt, or a potassium salt is preferable. In particular, potassium salts are preferred.
  • an alkyl thiol generated in a reaction system from a base such as sodium hydroxide or potassium hydroxide and a lower alkyl thiol is used.
  • Alkali metal salts can also be used.
  • an alkylating agent is added to the reaction system, the yield is improved, which is preferable.
  • the alkylating agent include an alkyl halide, a dialkyl carbonate, an alkyl sulfonate, and a dialkyl sulfate.
  • a potassium salt of an alkyl thiol generated in a reaction system by introducing an alkyl thiol into dimethyl sulfoxide of potassium hydroxide. More preferred is the addition of dialkyl carbonate.
  • the alkylthioating agent attacks the alkyl group adjacent to the sulfur in the product, and a disulfide compound of biphenylthiol / biphenyl, which is a dealkylated product, is produced as a by-product, resulting in a low yield.
  • This step is a step of obtaining the compound (IV) by treating the compound (IVa) with an acid.
  • N-Methylpyrrolidinone-water mixed solvent N-Methylpyrrolidinone-water mixed solvent, ethyl acetate-water mixed solvent, isopropyl acetate pill-water mixed solvent, isoptyl acetate-water mixed solvent, normal butyl acetate-water mixed solvent, etc.
  • N-methylpyrrolidinone-ice mixed solvent acetone-water mixed solvent, acetonitrile-water mixed solvent, methanol-water mixed solvent, ethyl acetate, ethyl acetate-hexane mixed solvent
  • the compound (IV) can be obtained as crystals from a solvent such as a solvent, a mixed solvent of tetrahydrofuran-water, a mixed solvent of dimethylformamide and water, a mixed solvent of dimethylacetamide-water, and a mixed solvent of dimethylsulfoxide water.
  • a mixed solvent of N-methylpyrrolidinone-water and acetate-water is preferable.
  • This step is a step of converting a sulfonic acid (IV) as a starting material into a sulfonyl halide compound (II) with a halogenating agent.
  • the halogenation reaction means this step and the tenth step.
  • the compound (I) can be obtained by performing the post-treatment performed.
  • the reaction can be carried out without solvent.
  • halogenating agent examples include thionyl chloride, sulfuryl chloride, oxychlorinated phosphorus, pentachloride linole, linyl trichloride, thionyl bromide, sulfuryl bromide, oxybromide, pentabromide, Examples include phosphorus tribromide, chlorine, and bromine. Thionyl chloride or oxychlorinated chloride are preferred.
  • This step is a step of capping using a sulfonyl compound (II) and a compound (III) as starting materials by using the Schotten-Bamann method.
  • the amidation reaction means this step.
  • Water-alcohol mixed solvent such as water-ethanol mixed solvent, water-propanol mixed solvent, water-isopropanol mixed solvent, water-butanol mixed solvent, water-isobutanol mixed solvent, water-sec-butanol mixed solvent, N, N —Dimethylformamide, N, N—Dimethylacetamide, dimethylsulfoxide, etc. in a solvent such as 0.9 to 2 equivalents, preferably 1.0 to 1.2 equivalents of compound (III).
  • the compound (II) in the presence of 2 to 10 equivalents, preferably 2 to 3 equivalents of a base at —20 ° C. to 30 ° C., preferably—5 ° C. to 10 ° C. for 1 to 20 hours ,
  • the compound (I) can be obtained by reacting the mixture for 1 hour to 3 hours, preferably, and performing a usual post-treatment.
  • a mixed solvent of acetate and water is preferable.
  • acetone: water 5: 1 to 1: 5 is preferable.
  • 2: 1 to 1: 2 is preferred.
  • Examples of the base include sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, cesium carbonate, cesium hydrogencarbonate, lithium carbonate, lithium hydrogencarbonate, rubidium carbonate, rubidium hydrogencarbonate, and water.
  • Inorganic bases such as lithium oxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, and ammonium carbonate; and alkali bases such as triethylamine, triptylamine, and diisoprovirethylamine. 3ammin and the like are exemplified.
  • Sodium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, triethylamine and the like are preferred.
  • the sulfonamide derivative having a biphenyl skeleton produced in this step has very poor solubility.
  • the solubility is easily isolated.
  • a large amount of solvent and heating are required due to the poor solubility.
  • Increasing the amount of solvent has a significant effect on yield and cost in the case of industrial production.
  • the impact on the environment is great.
  • by heating a part of the asymmetric carbon in the amino acid portion undergoes racemization. Even if a trace amount of optical isomers is produced, it can pose serious problems in developing pharmaceuticals.
  • This step is a step of coupling an arylpoic acid derivative (VI) and an aryl halide (VII) as starting materials to synthesize a biphenyl compound.
  • the carbon-carbon bond reaction means this step.
  • biphenyl halide (VII) in the presence of from 0.001 to 0.5 equivalents, preferably from 0.02 to 0.1 equivalents of the catalyst, 0.8 to 5 equivalents of biphenyl halide (VII) in a solvent.
  • the compound (IVa) can be obtained by reacting at C to 100 ° C for 1 hour to 30 hours, preferably 1.5 hours to 5 hours, and performing a usual post-treatment. .
  • the solvent examples include solvents such as benzene, toluene, N, N-dimethylformamide, dimethoxetane, tetrahydrofuran, dioxane, methanol, and ethanol, or a mixed solvent of these solvents and water. Particularly, dioxane, a mixed solvent of dimethoxetane-ethanol and a mixed solvent of dimethoxetane-ethanol-water are preferred.
  • Catalysts include palladium black, palladium monocarbon, palladium chloride (11), palladium (II) bisbenzonitrile, palladium (II) bisacetonitrile, palladium bromide, (11), iodide Palladium (11), palladium oxide (II), palladium sulfide (II), palladium acetate (II), palladium propionate (II), palladium sulfate (II), palladium hydroxide (II), palladium cyanide ( II), palladium trifluoroacetate (11), bistriphenylphosphine palladium chloride (II), and tetrakis (triphenylphosphine) palladium (0). Tetrakis (triphenylphosphine) palladium (0) and bistriphenylphosphine palladium chloride (I) are preferred.
  • Examples of the basic substance include sodium hydroxide, sodium methoxide, and hydroxylated water. , Ammonia, lithium hydroxide, cesium hydroxide, rubidium hydroxide, norium hydroxide, lithium methoxide, potassium methoxide, cesium methoxide, sodium ethoxide, lithium ethoxide, potassium ethoxide, Cesium ethoxide, lithium carbonate, lithium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, rubidium carbonate, rubidium bicarbonate, cesium carbonate, cesium bicarbonate, etc. Can be Sodium carbonate is preferred.
  • This step is a step for lower alkylation of a biphenyl thiol compound (VIII) as a starting material.
  • the alkylation reaction means this step.
  • Solvents such as N-methylpyrrolidine, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, dioxane, dimethoxetane, or a mixed solvent of these solvents and water
  • compound (VIII) and 1 to 20 equivalents, preferably 1 to 5 equivalents of an alkylating agent such as a lower alkyl halide, dialkyl carbonate, dialkyl sulfate, etc. at 120 ° C. to 100 ° C.
  • the compound (IVa) is reacted by reacting at 0 ° C to 50 ° C for 0.5 to 20 hours, preferably for 1 hour to 5 hours, and performing a usual post-treatment. Obtainable.
  • the starting material biphenyl compound (IX) is sulfonated to obtain biphenylsulfonic acid (IV).
  • This step is a step of converting the sulfonate (IVa) to a sulfonyl halide compound (II) by a halogenating agent.
  • the halogenation reaction means this step and the fifth step. The reaction can be carried out under the same conditions as in the fifth step.
  • D-phenylalanine (13R) 40 mg (0.24 mmo 1) to sodium carbonate 64 mg (0.6 mmo 1), ice 0.6 mL and acetone 0.6 mL Add Then, it was cooled to about 0 ° C. To this solution, 60 mg (0.2 mmol) of compound (7) was added, and the mixture was stirred at about 0 ° C for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. After drying, 71 mg (yield 83%) of the compound (I-16R) was obtained.
  • a compound having a biphenyl group substituted with a lower alkylthio group can be produced simply and economically.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de production d'un composé de la formule générale (IV) ou bien un sel ou un solvate de celui-ci, caractérisé en ce qu'un composé de la formule générale (V) ou bien un sel ou un solvate de celui-ci est soumis à une réaction pour obtenir une conversion en un alkylthio, dans lesquelles R1 représente un alkyle inférieur substitué ou non substitué, et X2 représente un halogène.
PCT/JP2003/006659 2002-05-30 2003-05-28 Procede de production d'un compose ayant un groupe biphenyle auquel est substitue un groupe alkylthio inferieur WO2003101944A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003241826A AU2003241826A1 (en) 2002-05-30 2003-05-28 Process for producing compound having biphenyl group substituted with lower alkylthio group

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2002-157935 2002-05-30
JP2002157935 2002-05-30

Publications (1)

Publication Number Publication Date
WO2003101944A1 true WO2003101944A1 (fr) 2003-12-11

Family

ID=29706473

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2003/006659 WO2003101944A1 (fr) 2002-05-30 2003-05-28 Procede de production d'un compose ayant un groupe biphenyle auquel est substitue un groupe alkylthio inferieur

Country Status (2)

Country Link
AU (1) AU2003241826A1 (fr)
WO (1) WO2003101944A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008066033A1 (fr) * 2006-11-29 2008-06-05 Hokko Chemical Industry Co., Ltd. Dérivé de benzène substitué par alkylthio et son procédé de fabrication

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0496396A2 (fr) * 1991-01-24 1992-07-29 Sumitomo Seika Chemicals Co., Ltd. Dérivé d'acide 2,5-dichlorophénylthioglycolique et procédé pour sa préparation
US5166460A (en) * 1991-04-01 1992-11-24 Sink James W Organ stop action valve mechanism
EP0708087A1 (fr) * 1994-10-18 1996-04-24 Rohm And Haas Company Procédé pour la préparation d'un composé benzénique
JPH11246527A (ja) * 1998-03-02 1999-09-14 Shionogi & Co Ltd Ｍｍｐ−８阻害剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0496396A2 (fr) * 1991-01-24 1992-07-29 Sumitomo Seika Chemicals Co., Ltd. Dérivé d'acide 2,5-dichlorophénylthioglycolique et procédé pour sa préparation
US5166460A (en) * 1991-04-01 1992-11-24 Sink James W Organ stop action valve mechanism
EP0708087A1 (fr) * 1994-10-18 1996-04-24 Rohm And Haas Company Procédé pour la préparation d'un composé benzénique
JPH11246527A (ja) * 1998-03-02 1999-09-14 Shionogi & Co Ltd Ｍｍｐ−８阻害剤

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008066033A1 (fr) * 2006-11-29 2008-06-05 Hokko Chemical Industry Co., Ltd. Dérivé de benzène substitué par alkylthio et son procédé de fabrication

Also Published As

Publication number Publication date
AU2003241826A1 (en) 2003-12-19

Similar Documents

Publication Publication Date Title
TW200819418A (en) Biaryl sulfonamide derivatives
JP2003171365A (ja) モナティン類及びその製造中間体の製造方法並びに新規中間体
Han et al. A convergent route to substituted azetidines and to Boc-protected 4-aminomethylpyrroles
WO2005105755A1 (fr) Processus de production de 5-difluorométhoxy -4-thiométhylpyrazoles
JP5610599B2 (ja) Ｎ−フェニル−ｎ’−フェニルスルホニルピペラジン誘導体の製造方法
TWI343909B (en) Process for making galantamine
WO2003101944A1 (fr) Procede de production d'un compose ayant un groupe biphenyle auquel est substitue un groupe alkylthio inferieur
JP4323718B2 (ja) 置換アルキルアミン又はその塩の製造方法
JP5109081B2 (ja) アルケンスルホン酸塩を用いたチオカルボアルキルアルカンスルホン酸塩、メルカプトアルカンスルホン酸塩およびジチオビス（アルカンスルホン酸）塩の製造方法
WO2004113258A1 (fr) Reaction formant une liaison carbone carbone
BR112020013985A2 (pt) novos processos e intermediários para a preparação de estimulantes de guanilato ciclase solúvel
WO2008050661A1 (fr) Procédé servant à produire un cristal de complexe asymétrique du cuivre
WO2002068382A1 (fr) Processus de preparation de derives de phenethylamine a substitution sulfamyle
CN113292479A (zh) 一种5-氮杂螺[2．4]庚烷及其盐的制备方法
WO1998057923A1 (fr) Nouveau procede de preparation
TWI302911B (en) Process for production of substituted alkylamine derivative
JP4886948B2 (ja) ビフェニルエチルアミン誘導体およびその製造方法
CA2456531C (fr) Procede de preparation de derives de 4-(imidazol-1-il)benzenesulfonamide
WO2012027951A1 (fr) Intermédiaire utilisé pour la préparation du médicament imipénème, son procédé de préparation et son utilisation
JP2000297072A (ja) パラおよび／またはメタ−置換されたシアノフェニルアラニン誘導体の新規な製造方法
JP2009114077A (ja) アルキルカルボニルチオ置換アルカンの製造方法
KR20050017776A (ko) 글리메피라이드의 제조방법
WO2002064623A1 (fr) Procede de preparation de derives peptidiques
JP2005239630A (ja) ハロゲン化アリールの新規なアルキルチオ化方法
JP2524793B2 (ja) ４−チオ置換フェノ―ル化合物の製造方法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP