WO2004113258A1 - Reaction formant une liaison carbone carbone - Google Patents

Reaction formant une liaison carbone carbone Download PDF

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Publication number
WO2004113258A1
WO2004113258A1 PCT/JP2004/008523 JP2004008523W WO2004113258A1 WO 2004113258 A1 WO2004113258 A1 WO 2004113258A1 JP 2004008523 W JP2004008523 W JP 2004008523W WO 2004113258 A1 WO2004113258 A1 WO 2004113258A1
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formula
general formula
carbon
salt
solvate
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PCT/JP2004/008523
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English (en)
Japanese (ja)
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Masaaki Uenaka
Shuhei Koshida
Makoto Kii
Shoji Shinomoto
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Shionogi & Co., Ltd.
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Publication of WO2004113258A1 publication Critical patent/WO2004113258A1/fr

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    • 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
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
    • C07C25/18—Polycyclic aromatic halogenated hydrocarbons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms

Definitions

  • the present invention relates to a Suzuki coupling suitable for an industrial process using an aqueous solvent, using economical palladium-carbon as a catalyst, considering the environment.
  • the present invention also relates to a more versatile Suzuki coupling in an aqueous solvent to which diols are added and catalyzed by palladium on carbon.
  • Non- Patent Document 1 The reaction of forming a carbon-carbon bond by reacting an aromatic halide with an aromatic boronic acid (or boronic ester) in the presence of a palladium catalyst is generally called Suzuki coupling (non- Patent Document 1).
  • This reaction is indispensable for the synthesis of biaryl sulfide compounds useful as liquid crystals and pharmaceuticals.
  • MMP inhibitors such as the following aryl-heteroarylsulfonamide derivatives (Patent Documents 1 and 2, Non-Patent Documents 2 and 3)
  • Bistriphenylphosphine palladium dichloride ((PP) PdCl) and the like are often used, and an organic solvent such as toluene is often used as a solvent.
  • organic solvent such as toluene
  • Patent Document 3 Non-patent Document 4
  • the substrate is limited to a compound having a phenolic hydroxyl group.
  • Non-Patent Document 5 reports Suzuki Riki coupling between a phenyl derivative having a carboxymethyl group and a phenylboronic acid derivative. However, the ratio of water: isopropanol is 8: 1, and the ratio of alcohol is high.
  • the substrate used in these reactions is characterized by having a hydrophilic group such as a hydroxyl group or a carboxy group as a substituent, and a substrate having only a hydrophobic group is disclosed or suggested. Not.
  • Non-Patent Document 6 describes a reaction in which ethylene glycol is added to a toluene / water-based solvent, but there is no description of the effect of the addition of a diol on the yield. In particular, there is no description of improving the yield by adding a diol in an aqueous solvent in the presence of a palladium-carbon catalyst, or that the reaction has a wide range of applications without using a substituent.
  • Patent Document 1 International Publication No. 97/27174 pamphlet
  • Patent Document 2 US Pat. No. 5,756,545
  • Patent Document 3 JP 2003-128608 A
  • Non-Patent Document 1 Norio Takaura, Akira Suzuki et al., Chemical Reviews 1995, Vol. 95, No. 7, p.2457-2483
  • Non-patent Document 2 Yoshinori Tamura et al., Journal of Medicinal Chemistry (J. Med. Chem.) 1998, Vol. 41, No. 4, p. 640-649
  • Non-Patent Document 3 Patrick M. O 'Brien et. Al., Journal of Medicinal Chemistry (J. Med. Chem.) 2000, Vol. 43, No. 2,
  • Non-Patent Document 4 Shunichi Hirao et al., Journal of Organic Chemistry (J. Org. Chem.) 2002, Vol. 67, No. 8, p.2721-2722
  • Non-Patent Document 5 D. Gala et. Al., Organic Process Researcher! ⁇ Aberoffment (Organic Process Research & Development) 1997, ⁇ ⁇ , p.163-164
  • Non-Patent Document 6 Christian Lieke et al., (Christian. Liek et. Al.) Zeitschrift fur Naturforschung B 1999, Vol. 54, No. 12, p. 1532 1542
  • R 1 is lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, honolemil, acyl, acyloxy, halogen, halo-lower alkyl, halo-lower alkyloxy, nitro, carboxy, snorejo, lower alkyloxycarbonyl, Lower alkynolesulfonyl, lower alkylsulfonyloxy, optionally substituted aminocarbonyl, optionally substituted aminocarbonyl, optionally substituted aryl, or optionally substituted heteroaryl; R 2 and R 2 'is simultaneously hydrogen atom or a lower alkyl, or R 2 and R 2' it may also form a 3 to 8-membered ring together with the oxygen atom connexion adjacent such together les,; Z 1 is - Ji 11: .!
  • R 1 1 is as defined the hydrogen atom or R 1, R 11
  • m is an integer from 0 to 3, when the above m power 3 ⁇ 4, the compound represented by R 1 is selected independently)
  • the Salts, or solvates thereof and
  • R ° is lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, honolemil, acyl, acyloxy, halogen, halo-lower alkyl, halo-lower alkyloxy, nitro, carboxy, snorejo, lower alkyloxycarbonyl, Lower alkynolesulfonyl, lower alkylsulfonyloxy, optionally substituted aminyl, optionally substituted aminocarbonyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 3 is Hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl ;
  • R 4 is hydrogen atom, lower alkyl, Ararukiru, hetero Reel alkyl or Ashiru,; Y during hydroxy or lower Arukiruokishi 1 is
  • n are the same as defined above), a salt thereof, or a solvate thereof.
  • n is the same as defined in 1)
  • R °, X 1 and Z 2 have the same meaning as in 1); p has the same meaning as in 7)), a salt thereof, or a solvate thereof.
  • lower alkyl used alone or in combination with other terms includes a straight-chain or branched-chain monovalent hydrocarbon group having 118 carbon atoms.
  • C1-C6 alkyl is used. More preferably, C1-C4 alkyl is used. More preferably, C1-C3 alkyl is mentioned.
  • lower alkyl for R 1 is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like.
  • R 2 and R 2 ′ methyl, ethyl, n-propyl, isopyryl and the like are preferable. Further, methyl is preferred.
  • methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like are preferable.
  • Methyl, ethyl, isopropyl, isobutyl, sec-butyl are more preferred.
  • methyl ethyl, n-propyl, n-butyl and the like are preferable. Masire, Further, methyl is preferred.
  • R 6 and R 6 ′ methyl, ethyl, n-propyl, isopyl pill and the like are preferable. Further, methyl is preferred.
  • aryl used alone or in combination with other terms includes a monocyclic or condensed cyclic aromatic hydrocarbon.
  • phenyl, 11-naphthine, 2-naphthyl, anthryl and the like can be mentioned.
  • the term "arano quinole” is obtained by substituting the above “lower alkyl” by one or more of the above “aryl”, and these may be substituted at all possible positions.
  • benzene e.g, 2-phenylethyl
  • phenylpropyl eg, 3_phenylpropyl
  • naphthylmethyl eg, 1-naphthylmethyl, 2-naphthylmethyl, etc.
  • anthrylmethyl eg, 9-anthrylmethyl and the like.
  • R 3 and R 4 benzyl, phenylethyl, naphthylmethyl and the like are preferable.
  • Benginore is preferred.
  • heteroaryl used alone or in combination with other terms refers to an arbitrarily selected 5- to 6-membered ring containing one or more oxygen, sulfur or nitrogen atoms in the ring. Which may be fused with cycloalkyl, aryl, non-aromatic heterocycle, or other heteroaryl, which may be fused at all possible positions.
  • pyrrolyl eg, 1-pyrrolyl, 2_pyrrolyl, 3-pyrrolyl
  • furyl eg, 2-furyl, 3_furyl
  • phenyl eg, 2_phenyl, 3_phenyl
  • imidazolinole eg, 2_imidazolyl, 4-imidazolyl
  • pyrazolyl eg, 1-pyrazolyl, 3-virazolinole
  • isothiazolyl eg, 3-isothiazolyl
  • isoxazolyl eg, 3-isoxazozolyl
  • oxazolyl eg, 2-oxazolyl
  • Thiazolyl for example, 2-thiazolyl
  • pyridyl for example, 2_pyridinole, 3_pyridinole, 4_pyridyl
  • pyrazur for example, 2-pyrazuryl
  • pyrimidinyl for example, 2_pyrimidyl
  • heteroarylalkyl means one or more of the above “heteroaryl” substituted at any position of the above “lower alkyl”, and these may be substituted at all possible positions.
  • thiazolylmethyl for example, 4_thiazolylmethyl
  • thiazolylethyl for example, 5_thiazolyl-2-ethyl
  • benzothiazolylmethyl for example, (benzothiazonole_2_yl) methyl
  • indolylmethyl for example, ( Indole—3—
  • heteroarylalkyl for R 3 , indolylmethyl (eg, indolinole-3-ylmethyl), imidazolylmethyl (eg, imidazole-5-ylmethyl) and the like are preferable. Indore no_3_ylmethyl is preferred.
  • heteroarylalkyl for R 4 , indolylmethyl (eg, indole-no_3_ylmethyl) and the like are preferable.
  • the “lower alkyloxy” includes methyloxy, ethyloxy, n-propyl pyroxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy and the like.
  • methyloxy, ethyloxy, n-propyloxy, isopropyloxy and n-butyloxy are exemplified.
  • lower alkylthio includes methylthio, ethylthio, n-propylthio and the like.
  • acyl used alone or in combination with other terms, includes an alkylcarbonyl wherein the alkyl moiety is the above “lower alkyl” or an arylcarbonyl wherein the aryl moiety is the above “aryl”. I do. For example, acetyl, propionyl, benzoyl and the like can be mentioned. “Lower alkyl” and “aryl” may be substituted by the respective substituents described below.
  • examples of "asyloxy” include acetyloxy, propionyloxy, benzoyloxy and the like.
  • halogen refers to fluorine, chlorine, bromine, and iodine. Preference is given to chlorine and bromine. More preferably, chlorine is used.
  • ⁇ halo lower alkynole '' used alone or in combination with other terms refers to the above-mentioned ⁇ lower alkyl '' substituted at 118 places, preferably at 115 places by the above-mentioned ⁇ halogen ''.
  • ⁇ halo lower alkynole '' used alone or in combination with other terms refers to the above-mentioned ⁇ lower alkyl '' substituted at 118 places, preferably at 115 places by the above-mentioned ⁇ halogen ''.
  • trifluoromethyl, trichloromethyl, difluoroethyl, trifluoroethyl, dichloroethynole, trichloroethyl and the like can be mentioned.
  • trifluoromethyl is used.
  • halo lower alkyl for R 5 , trifluoromethyl is preferable.
  • halo lower alkyloxy includes trifluoromethyloxy and the like.
  • lower alkyloxycarbonyl includes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl and the like.
  • the “lower alkylsulfonyl” includes methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like.
  • the “lower alkylsulfonyloxy” includes methanesulfonyloxy, ethanesulfonylsulfonyloxy, propanesulfonyloxy and the like.
  • the term “optionally substituted amino” used alone or in combination with other terms refers to an unsubstituted amino or the above-mentioned “lower alkyl", “aralkyl”, “heteroarylalkyl”, Or amino substituted one or two times with “acyl”.
  • amino, methinoleamino, dimethylamino, ethylmethylamino, getylamino, benzylamino, acetylamino, benzoylamino and the like can be mentioned.
  • amino, methylinoamino, dimethylamino, ethylmethylamino, getylamino, and acetylamino are exemplified.
  • the “optionally substituted aminocarbonyl” includes aminocarbyl (forcebamoyl), methylaminocarbonyl, dimethylaminocarbonyl, ethylmethylaminocarbonyl, getylaminocarbonyl and the like.
  • amino carbonyl and dimethylamino carbonyl are mentioned.
  • examples of the substituent in the "optionally substituted lower alkyl” include cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), hydroxy, and lower alkyloxy (for example, methoxy).
  • aryl eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
  • lower alkenyl eg, bier, propenyl, butenyl
  • Lower alkynyl ethynyl, propyninole
  • hydroxy lower alkyloxy (eg, methoxy, ethoxy, t-butoxy)
  • mercapto lower alkylthio (eg, methylthio, ethylthio), halogen, nitro, cyano, carboxy, sulfo, lower alkyl Oxycarbonyl (eg, methoxycarbonyl,
  • R 3 is substituted, good Rere Ariru be", "substituted been, even if good records, Heteroari Le”, “may be substituted Ararukiru”, and "to which may be substituted Hydroxy or halogen is preferred as the substituent in “teroarylalkyl”. Also preferred are “unsubstituted aryl”, “unsubstituted heteroaryl”, “unsubstituted aralkyl”, and “unsubstituted heteroarylalkyl”.
  • R 2 and R 2 ' may be taken together to form a 38-membered ring containing an adjacent oxygen atom
  • R 6 and R 6 ' are taken together. May form a 38-membered ring each containing an adjacent oxygen atom ", and includes the following rings.
  • diol as used herein means an alcohol having two hydroxyl groups bonded to different carbon atoms in C2-C6, preferably C2-C4 alkanediyl. Examples include ethylene glycol, 2,3_butanediol, 2,3_dimethyl-2,3_butanediol, and 1,3-propanediol. Ethylene glycol is preferred.
  • BEST MODE FOR CARRYING OUT THE INVENTION [0018] When referring to a “compound”, the compound is not limited to a specific isomer, but includes all possible isomers (eg, optical isomers) and racemates. Further, a pharmaceutically acceptable salt or a solvate thereof is also included.
  • salt of the compound used in the present invention refers to alkali metals (lithium, sodium, potassium, cesium, etc.), alkaline earth metals (magnesium, calcium, barium, etc.), ammonium, organic bases and amino acids.
  • organic acids acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • inorganic acids hydroochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.
  • Contains salt can be formed by a commonly used method.
  • 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 coupling the compound represented by the general formula (IV) and the compound represented by the general formula (V) as starting materials using the Schotten-Baumann method.
  • the solvent a mixed solvent of acetone and water is preferable.
  • the base include sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, cesium carbonate, cesium hydrogencarbonate, lithium carbonate, lithium hydrogencarbonate, rubidium carbonate, and rubidium hydrogencarbonate.
  • inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, norrebidium hydroxide, cesium hydroxide and ammonium carbonate, and tertiary amines such as triethylamine, tributylamine and diisopropylethylamine.
  • Sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, triethylamine, etc. are preferred (second step).
  • This step is a step of performing a coupling reaction in the presence of palladium-carbon on the compound represented by the general formula (II) and the compound represented by the general formula (III) as starting materials.
  • the solvent water or a mixed solvent of water and an organic solvent is preferable.
  • Water or water split A mixed solvent with an organic solvent having a high compatibility is more preferable.
  • the mixing ratio of water and the organic solvent is preferably 100: 0-85: 15, more preferably 100: 0-90: 10, even more preferably 100: 0-93: 7, and particularly preferably.
  • the solvent is water. In particular, water is preferred.
  • the organic solvent of the mixed solvent the force due to the solubility of the substrate S, benzene, toluene, N, N-dimethylphenol, amide, dimethoxyethane, tetrahydrofuran, dioxane, methanol, ethanol, isopropanol, and the like are preferable.
  • Basic substances include sodium hydroxide, sodium methoxide, potassium hydroxide, ammonia, lithium hydroxide, cesium hydroxide, rubidium hydroxide, barium hydroxide, lithium methoxide, potassium methoxide, cesium methoxide, and sodium ethoxide.
  • Sodium carbonate, potassium carbonate and disodium hydrogen phosphate are preferred.
  • the palladium carbon catalyst preferably contains water.
  • the water content is preferably 70% -30%. Further, 60% to 40% is preferable.
  • the content of palladium carried on the palladium carbon is preferably 13% to 1%. 7% -3% is more preferred.
  • 0.1 to 5 equivalents, preferably 0.3 to 2 equivalents of a diol such as ethylene daryl it is preferable to add 0.1 to 5 equivalents, preferably 0.3 to 2 equivalents of a diol such as ethylene daryl to the reaction system in order to suppress a side reaction.
  • Solvent power W Sopropanol- 17 (main) mixed solvent, 5% palladium-carbon catalyst containing water as the catalyst, and reaction conditions in which the basic substance is potassium carbonate are preferable.
  • the reaction conditions, which are in the presence of, are preferred.
  • This step is a step of performing a coupling reaction in the presence of a diol using a compound represented by the general formula (VI) and a compound represented by the general formula (VII) as starting materials.
  • water or a mixed solvent of water and an organic solvent is preferable.
  • Water or a mixed solvent with an organic solvent having a high percentage of water is more preferable.
  • the mixing ratio of water and the organic solvent is preferably 100: 085: 15, more preferably 100: 0-90: 10, even more preferably 100: 0-93: 7, and particularly preferably a solvent.
  • the organic solvent of the mixed solvent benzene, toluene, N, N-dimethylformamide, dimethoxyethane, tetrahydrofuran, dioxane, methanol, ethanol, isopropanol, etc. are preferred.
  • Examples of the basic substance and the nodium-carbon catalyst include those used in the second step.
  • the diols include ethylene glycol, 2,3_butanediol, 2,3_dimethyl-2,
  • the pH of the reaction solution is usually pH 7-11, but the type of boronic acid represented by the general formula (VI) is Depending on the pH, pH 4-6 may be optimal. In such a case, the reaction is preferably performed in the presence of acetic acid, sodium dihydrogen phosphate or sodium monohydrogen phosphate.
  • reaction conditions in which the solvent is an aqueous solvent, the catalyst is 5% palladium-carbon containing water, the basic substance is disodium hydrogen phosphate, and the diol is ethylene glycol are more preferable.
  • This step is a step of performing a coupling reaction using the compound represented by the general formula (IX) and the compound represented by the general formula (VII) as starting materials.
  • boronic ester represented by the general formula (IX) a commercially available product can be used.
  • References (Sudersan M. Tuladhar et. Al.), Tetrahedron Letters 1992, Vol. 33, No. 2, p. 265-268, etc. Can also be synthesized from the reaction of a boronic acid derivative with an alcohol. Further The compound can also be synthesized by the method described in the literature (Miyaura et al., Journal of Organic Chemistry (J. Org. Chem.) 1995, Vol. 60, No. 23, p. 7508-7510).
  • Examples of the solvent, basic substance, catalyst and the like include the solvents, basic substances, catalysts and the like described in the second and third steps.
  • reaction conditions in which the solvent is an aqueous solvent, the catalyst is 5% palladium-carbon containing water, and the basic substance is disodium hydrogen phosphate.
  • Disodium hydrogen phosphate (1.765 g, 12.4 mmol) was dissolved in water (30 mL), and 4_bromobenzoic acid (la, 1.00 g, 4.97 mmol) and phenylboronic acid (2a, 0.728 g, 5.97 mmol) was added at room temperature.
  • the suspension was mixed with ethylene glycol (3.0 ml, 53.8 mmol) and 5% palladium-carbon (2 mg, 0.456 ol) as a catalyst, and stirred at 95 ° C under a nitrogen stream for 8 hours.
  • Disodium hydrogenphosphate (1.765 g, 12.4 mmol) was dissolved in water (30 ml), and 4_bromobenzoic acid (la, 1.00 g, 4.97 mmol), phenylboronic acid (2a, 0.728 g, 5.97 mmol) was added at room temperature.
  • Sodium bromide (0.512 g, 4.98 mmol), ethylene glycol (3.0 ml, 53.8 mmol), 5% palladium-carbon (2 mg, 0.456 nmol) were added to the suspension, and the mixture was stirred at 95 ° C for 8 hours under a nitrogen stream. Stirred.
  • Disodium hydrogen phosphate (1.765 g, 12.4 mmol) was dissolved in water (30 ml), and 4_bromobenzoic acid (la, 1.00 g, 4.97 mmol) and phenylboronic acid (2a, 0.728 g, 5.97 mmol) was added at room temperature. 2, 3-butanediol (3.0 ml, 33.1 mmol) and 5% palladium-carbon (2 mg, 0.456 nmol) were added to the suspension, and the mixture was stirred at 95 ° C under a nitrogen stream for 8 hours.
  • Table 1 summarizes the results of Examples 13 and 13 and Comparative Example 1. Even when the reaction does not proceed with phenylboronic acid alone, the reaction proceeds smoothly in the presence of the diol, and the desired product is obtained in good yield. In particular, in the presence of diol and sodium bromide, the yield is significantly improved.
  • Disodium hydrogen phosphate (1.765 g, 12.4 mmol) was dissolved in water (30 ml), and 4_bromobenzoic acid (la, 1.00 g, 4.97 mmol) and phenylboronic acid ethylene glycol ester (2b, 0.883 g, 5.97 mmol) was added at room temperature.
  • 4_bromobenzoic acid la, 1.00 g, 4.97 mmol
  • phenylboronic acid ethylene glycol ester (2b, 0.883 g, 5.97 mmol
  • the reaction solution was allowed to cool to room temperature, 2 mol / L hydrochloric acid (10 ml) was added, the mixture was stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration.
  • Disodium hydrogenphosphate (1.765 g, 12.4 mmol) was dissolved in water (30 ml), and 4_bromobenzoic acid (la, 1.00 g, 4.97 mmol), phenylboronic acid 2,3 butanediol ester (2c, 1.051 g, 5.97 mmol) was added at room temperature.
  • the suspension was quenched with 5% palladium carbon (2 mg, 0.456 nmol) and stirred at 95 ° C. for 8 hours under a nitrogen stream.
  • the reaction solution was allowed to cool to room temperature, 2 mol / L hydrochloric acid (10 ml) was added, the mixture was stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration.
  • the obtained crude crystals were dissolved in tetrahydrofuran (100 ml), and a solution in which acetonitrile was added to 1 ml of the solution and the total amount was 50 ml was prepared. Using this solution, a quantitative test (UV 230 nm) was performed by HPLC. The yield of 4-bicarboxylic acid 3 was 86.6%.
  • Disodium hydrogen phosphate (1.765 g, 12.4 mmol) was dissolved in water (30 ml), and 4-bromobenzoic acid (la, 1.00 g, 4.97 mmol), 4-acetylphenylboronic acid (2d, 0.979 g, 5.97 mmol) was added at room temperature.
  • Sodium bromide (0.512 g, 4.98 mmol), ethylene glycol (3.0 ml, 53.8 mmol), 5% palladium on carbon (21 mg, 4.79 nmol) were added to the suspension, and the mixture was stirred at 95 ° C under a nitrogen stream for 1.5 hours. Stirred.
  • reaction solution was allowed to cool to room temperature, 2 mol / L hydrochloric acid (10 ml) was added thereto, and the mixture was stirred at room temperature for 30 minutes.
  • the precipitated crystals were collected by filtration and recrystallized from tetrahydrofuran Z-hexane to obtain the desired product (4, 1.142 g, 95.5%).
  • Disodium disodium hydrogen phosphate (1.786 g, 12.6 mmol) was dissolved in water (28 ml), and 4-bromoisole (lb, 0.63 ml, 5.03 mmol) and phenylboronic acid (2a, 0.736 g, 6.04 mmol) were added at room temperature. Added in. Sodium bromide (0.518 g, 5.03 mmol), ethylene glycol (2.8 ml, 50.2 mmol), 5% palladium-carbon (221 mg, 50.1 nmol) were added to the suspension, and the mixture was stirred at 95 ° C for 8 hours under a nitrogen stream. Stirred.
  • reaction solution was allowed to cool to room temperature, extracted twice with ethyl acetate (50 ml, 30 ml), and the organic layer was dried over magnesium sulfate.
  • the solvent was distilled off under reduced pressure, the residue was crystallized from methanol / water, and the obtained crude crystals were recrystallized from isopropanol Z water to obtain the desired product (5, 0.486 g, 52.5%). .
  • Disodium dihydrogen phosphate (1.783 g, 12.6 mmol) was dissolved in water (30 ml), and 4-bromoacetylethylbenzene (lc, 1.00 g, 5.02 mmol) and phenylenoboronic acid (2a, 0.735 g, 6.03 mmol) were added. Added at room temperature. To the suspension were added sodium bromide (0.517 g, 5.02 mmol), ethylene glycol (3.0 ml, 53.8 mmol), and 5% palladium on carbon (220 mg, 50.1 nmol), and the mixture was added with 95. The mixture was stirred under a nitrogen stream with C for 3 hours.
  • Disodium hydrogenphosphate (1.786 g, 12.6 mmol) was dissolved in water (28 ml), and 4-bromodisole (lb, 0.63 ml, 5.03 mmol), 4-acetylphenylboronic acid (2d, 0.990 g, 6.04 mmol) was added at room temperature.
  • Sodium bromide (0.518 g, 5.03 mmol), ethylene glycol (2.8 ml, 50.2 mmol) and 5% palladium on carbon (221 mg, 50.1 mmol) were added to the suspension, and the mixture was stirred at 95 ° C for 8 hours under a nitrogen stream. Stirred.
  • Disodium hydrogen phosphate (1.765 g, 12.4 mmol) was dissolved in water (30 ml), and 4_bromobenzoic acid (la, 1.00 g, 4.97 mmol) and 4_fluorophenylboronic acid (2e, 0.835 g, 5.97 mmol) was added at room temperature.
  • Sodium bromide (0.512 g, 4.98 mmol), ethylene glycol (3.0 ml, 53.8 mmol) and 5% palladium on carbon (21 mg, 4.79 nmol) were added to the suspension, and the mixture was stirred at 95 ° C for 2 hours under a nitrogen stream. Stirred.
  • the reaction solution was allowed to cool to room temperature, and the precipitated crystals were collected by filtration.
  • the crude product was recrystallized from ethyl acetate / hexane to obtain the desired product (8, 1.015 g, 95.2%).
  • reaction solution was allowed to cool to room temperature, extracted twice (150 ml, 100 ml) with ethyl acetate, and the organic layer was dried over magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the residue was crystallized from acetone / water to obtain the desired product (9, 0.502 g, 63.2%).
  • Disodium hydrogen phosphate (1.765 g, 12.4 mmol) was dissolved in water (30 ml), and 4-bromobenzoic acid (la, 1.00 g, 4.97 mmol) and 4-methylthiophenenylboronic acid (2f, 1.00 mmol) were dissolved. g, 5.97 mmol) at room temperature.
  • Sodium bromide (0.512 g, 4.98 mmol), ethylene glycol (3.0 ml, 53.8 mmol) and 5% palladium on carbon (221 mg, 50.1 nmol) were added to the suspension, and the mixture was stirred at 95 ° C for 28 hours under a nitrogen stream. Stirred.
  • reaction solution was allowed to cool to room temperature, extracted twice with ethyl acetate (150 ml, 100 ml), and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate / hexane to give the desired product (10, 0.268 g, 22.1%).
  • Disodium hydrogen phosphate (1.765 g, 12.4 mmol) was dissolved in water (30 ml), and 4_bromobenzoic acid (la, 1.00 g, 4.97 mmol) and 4_tolylboronic acid (2 g, 0.812 g, 5.97 g) were dissolved. mmol) at room temperature.
  • Sodium bromide (0.512 g, 4.98 mmol), ethylene glycol (3.0 ml, 53.8 mmol), 5% palladium-carbon (21 mg, 4.79 nmol) were added to the suspension, and the mixture was stirred at 95 ° C for 3 hours under a nitrogen stream. Stirred.
  • reaction solution was allowed to cool to room temperature, and 2 mol / L hydrochloric acid (10 ml) was stirred at room temperature for 30 minutes.
  • the precipitated crystals were collected by filtration and recrystallized from ethyl acetate / hexane to obtain the desired product (11, 0.969 g, 91.8%).
  • Disodium hydrogenphosphate (1.777 g, 12.5 mmol) was dissolved in water (26 ml), and 4-bromophenololebenzene (If, 0.55 ml, 5.01 mmol) and phenylboronic acid (2a, 0.733 g, 6.01 mmol) were added at room temperature. added.
  • sodium bromide 0.515 g, 5.01 mmol
  • ethylene glycol 2.6 ml, 46.6 mmol
  • 5% palladium on carbon (220 mg, 50.1 nmol). Stirred for hours.
  • the reaction solution was allowed to cool to room temperature and twice with ethyl acetate (200 ml, 100 ml), and the organic layer was dried over magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the residue was crystallized from methanol / water to obtain the desired product (12, 0.613 g, 71.1%).
  • the reaction solution was concentrated under reduced pressure, and the obtained slurry (108.4 g) was extracted with water (59 mL), acetone (2.8 mL), and ethyl acetate (57 mL). After the organic layer was extracted with water (13 mL), the aqueous layers were combined, acidified with concentrated hydrochloric acid (13 mL), and extracted with ethyl acetate (60 mL). The organic layer is washed with water (20 mL) and concentrated under reduced pressure. After dissolving the residue in isopropanol (26 mL), the solution was concentrated once more to obtain an isopropanol solution of compound 16 (25.0 g), and this solution was directly used in the next step. Purified samples for analysis were obtained by crystallization of acetone tonoleenca. Melting point: 123-125 ° C
  • Carbonic acid was added to a suspension of Compound 16 (25.0 g, Compound 14; isopropanol solution obtained from 38.0 mol) and Compound 2f (6.38 g, 1.0 eq) in isopropanol (7.8 mL) and water (128 mL). Potassium (13.1 g, 2.5 eq) was added in portions. Wet 5% palladium on carbon (51.5%, 2.5 g, 0.015 eq) was added to the suspension and the mixture was degassed by purging three times with vacuum-nitrogen. The mixture was heated at 7580 ° C for 5 hours, and then cooled to room temperature.
  • the filtrate was washed sequentially with ethyl acetate (50 mL, 30 mL), and the organic layer was back-extracted with water (30 mL).
  • 35% hydrochloric acid (3.8 mL) was added dropwise at about 25 ° C, and the pH was adjusted to 2.2.
  • the precipitated crystals were collected by filtration and washed with isopropanol / water (50 mL / 50 mL).
  • the crystals were dried to obtain crude IB (8.26 g).
  • the crystals were dissolved in tetrahydrofuran (50 mL), activated carbon (500 mg) was added, and the mixture was filtered. After concentrating the solvent, the precipitated crystals were collected by filtration and washed with cold isopropyl. Dried and purified I-B (8.2 g, 73.6%) was obtained.
  • Non-isolated method for intermediate D-valine (15, 8.4 g, 71.7 mmol, 1.1 eq) was dissolved in a 2% aqueous sodium hydroxide solution (129.6 g, 1.0 eq), and isopropanol (102 mL) was obtained.
  • Compound 6 (17 g, 65.0 mmol) was added at about 7 ° C, and the pH was maintained at 11 to 12 by adding a 17% aqueous sodium hydroxide solution (17.3 g, 1.1 eq). The reaction solution was stirred at around 7 ° C for 5 hours.
  • the reaction solution was concentrated to 127.9 g to distill off isopropanol, and a 3.7% aqueous sodium hydroxide solution (69.4 g, l.Oeq) was added.
  • Compound 2d (11.6 g, 70.6 mmol, 1.1 eq), acetic acid (5.84 g, 96.4 mmol, 1.5 eq), 5% palladium-carbon (51.6% wet) (7.07 g, 1.6 mmol, 0.025 eq) were added sequentially. 90. The temperature rose to C. The reaction solution was stirred at the same temperature for 4 hours.
  • the desired product and a solid containing water are obtained.
  • the moist solid is dissolved in acetone at 50 ° C. Filter off insolubles and wash with acetone / water (9/1). The filtrate and the washing solution are combined and treated with activated carbon. After filtering the activated carbon, it is washed with acetone / water (9/1). Slowly add water to the combined solution of filtrate and washings. After further stirring at 22 ° C for 20 minutes, water is added to the slurry at 22-24 ° C. After cooling the slurry to 18, filtration, washing with water and drying, a crude product is obtained. The crude product is recrystallized with tetrahydrofuran / acetone power to obtain the desired crystal (g).
  • An economical Suzuki coupling suitable for an industrial process using an aqueous solvent can be performed using palladium-carbon as a catalyst, considering the environment.
  • diols it is possible to improve the yield of Suzuki coupling in a nodium-carbon catalyst and aqueous system.

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

Abstract

L'invention concerne un procédé de production de composés représentés par la formule générale (I), leurs sels ou leur solvate provenant de composés par les formules générales (II) et (III), leurs sels et leurs solvates comprenant l'étape représentée par la formule de réaction (A) dans laquelle R0 désigne alkyle inférieur ou analogue ; R1 désigne alkyle inférieur ou analogue ; R2 et R2' désignent simultanément hydrogène ou analogue ; R3 désigne alkyle inférieur éventuellement substitué ou analogue ; R4 désigne hydrogène ou analogue ; X1 désigne halogéno ; Y désigne hydroxyle ou analogue ; Z1 désigne -CH=CH- ou analogue ; Z2 représente -CH=CH- ou analogue ; m désigne un entier compris entre 0 et 30 et n désigne un entier compris entre 0 et 2. Le procédé de cette invention est caractérisé en ce que la réaction est menée dans un solvant contenant de l'eau en présence d'un palladium-carbone.
PCT/JP2004/008523 2003-06-20 2004-06-17 Reaction formant une liaison carbone carbone WO2004113258A1 (fr)

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JP2009298727A (ja) * 2008-06-13 2009-12-24 Shiratori Pharmaceutical Co Ltd ビアリール化合物の製造方法
US8884034B2 (en) 2009-07-08 2014-11-11 Dermira (Canada), Inc. TOFA analogs useful in treating dermatological disorders or conditions
JP2016222661A (ja) * 2015-05-29 2016-12-28 北興化学工業株式会社 新規なヒドロキシフェニルボロン酸エステルとその製造方法、およびヒドロキシビフェニル化合物の製造法
US10457679B2 (en) 2015-09-17 2019-10-29 Astrazeneca Ab Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009298727A (ja) * 2008-06-13 2009-12-24 Shiratori Pharmaceutical Co Ltd ビアリール化合物の製造方法
US8884034B2 (en) 2009-07-08 2014-11-11 Dermira (Canada), Inc. TOFA analogs useful in treating dermatological disorders or conditions
US9434718B2 (en) 2009-07-08 2016-09-06 Dermira (Canada), Inc. TOFA analogs useful in treating dermatological disorders or conditions
US9782382B2 (en) 2009-07-08 2017-10-10 Dermira (Canada), Inc. TOFA analogs useful in treating dermatological disorders or conditions
JP2016222661A (ja) * 2015-05-29 2016-12-28 北興化学工業株式会社 新規なヒドロキシフェニルボロン酸エステルとその製造方法、およびヒドロキシビフェニル化合物の製造法
US10457679B2 (en) 2015-09-17 2019-10-29 Astrazeneca Ab Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer
US10882858B2 (en) 2015-09-17 2021-01-05 Astrazeneca Ab Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer
US11613539B2 (en) 2015-09-17 2023-03-28 Astrazeneca Ab Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors

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