WO2010041538A1 - Procédé de production d’un composé carbonyloxy - Google Patents

Procédé de production d’un composé carbonyloxy Download PDF

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WO2010041538A1
WO2010041538A1 PCT/JP2009/066022 JP2009066022W WO2010041538A1 WO 2010041538 A1 WO2010041538 A1 WO 2010041538A1 JP 2009066022 W JP2009066022 W JP 2009066022W WO 2010041538 A1 WO2010041538 A1 WO 2010041538A1
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compound
group
carbonyloxy
ethyl
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健次 田中
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株式会社トクヤマ
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Priority to JP2010532869A priority Critical patent/JP5441913B2/ja
Priority to CN2009801350565A priority patent/CN102149669A/zh
Publication of WO2010041538A1 publication Critical patent/WO2010041538A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen 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
    • C07C67/347—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 by addition to unsaturated carbon-to-carbon bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/62—Halogen-containing esters
    • C07C69/65—Halogen-containing esters of unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a novel method for producing a carbonyloxy compound produced using an aniline compound and an ⁇ , ⁇ -unsaturated carbonium compound as raw materials.
  • the present invention relates to a novel method for producing a carbonyloxy compound that is useful as a raw material for producing a drug substance or an intermediate used in the treatment of type 2 diabetes caused by insufficient insulin action.
  • a therapeutic agent that exhibits an excellent effect on type 2 diabetes caused by insufficient action of insulin such as pioglitazone, ciglitazone, and rosiglitazone (formula (10) shows the basic skeleton of the therapeutic agent) has conventionally been represented by the following formula: It is produced by a method via a carbonyloxy compound represented by (8).
  • the carbonyloxy compound represented by the formula (8) is produced by the Meerwein arylation reaction using the aniline compound represented by the formula (7).
  • This reaction is a reaction in which a diazonium salt produced by reacting a nitrite with an aniline compound represented by the formula (7) in the presence of hydrogen bromide and a carbonyl compound are reacted in the presence of a copper catalyst. It is. Journal of Medicinal Chemistry 35, 14, 2617-2626 (1992) Japanese Patent Publication No. 5-66956
  • An object of the present invention is to provide a method for producing a carbonyloxy compound with high yield and high purity.
  • a diazonium salt is synthesized by reacting an aniline compound and nitrite in the presence of an acid, and then Meerwein arylation using the diazonium salt and an ⁇ , ⁇ -unsaturated carbonyloxy compound in the presence of a copper catalyst. It has been found that, when a reaction is carried out, if a base having a specific acid dissociation index is present in the reaction system, side reactions are suppressed and a high-purity carbonyloxy compound can be produced in a high yield.
  • the present invention has been completed based on the above discovery.
  • R 2 is a hydrogen atom, an alkyl group, an alkenyl group or an aryl group.
  • R 3 is a hydrogen atom, an alkyl group, or an aryl group.
  • a method for producing a carbonyloxy compound comprising: In the carbonyloxy compound synthesis step, when the diazonium salt and the ⁇ , ⁇ -unsaturated carbonyloxy compound are reacted, a base having an acid dissociation index (pKa) at 25 ° C. of 7 or less is present in the reaction system. And a method for producing a carbonyloxy compound.
  • the carbonyloxy compound synthesis step it is preferable that 0.05 to 10 mol of the base is present per 1 mol of the diazonium salt.
  • the base is preferably a nitrogen-containing heterocyclic compound having an acid dissociation index (pKa) at 25 ° C. of 4 to 7.
  • the production method of the present invention includes a method for producing methyl 2-bromo-3- ⁇ 4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl ⁇ propionate, which is an intermediate of pioglitazone hydrochloride. This production method can effectively reduce side reactions.
  • the production method of the present invention comprises methyl 2-bromo-3- ⁇ 4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl ⁇ propionate produced according to the above production method in the presence of an alkali.
  • the present invention is characterized by reacting 5- ⁇ 4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl ⁇ -2-imino-4-thiazolidinone prepared according to the above method with hydrogen chloride.
  • 5- ⁇ 4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl ⁇ thiazolidine-2,4-dione hydrochloride is produced.
  • a high purity carbonyloxy compound can be produced in a high yield by the presence of a predetermined base in the Meerwein arylation reaction. Since the carbonyloxy compound produced by the high-yield production method of the present invention has a high purity, it is particularly useful as a raw material or intermediate for a drug substance. Therefore, this manufacturing method has very high industrial utility value.
  • Methyl 4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl ⁇ propionate can be produced in high yield and purity.
  • the method for producing a carbonyloxy compound represented by formula (3) of the present invention comprises reacting an aniline compound represented by formula (1) with a nitrite in the presence of hydrogen chloride or hydrogen bromide to form a diazonium salt. And a diazonium salt produced in the diazonium salt synthesis step and an ⁇ , ⁇ -unsaturated carbonyloxy compound represented by the formula (2) in the presence of a copper catalyst, A carbonyloxy compound synthesis step for synthesizing the carbonyloxy compound represented by the formula (3) is included.
  • the method for producing the carbonyloxy compound represented by the formula (3) is such that the acid dissociation index at 25 ° C. is obtained when the diazonium salt is reacted with the ⁇ , ⁇ -unsaturated carbonyloxy compound in the carbonyloxy compound synthesis step.
  • a base having (pKa) of 7 or less is present in the reaction system.
  • Diazonium salt synthesis step synthesizes a diazonium salt derived from the aniline compound by reacting the aniline compound represented by the formula (1) with nitrite in the presence of hydrogen chloride or hydrogen bromide. It is a process to do.
  • R 1 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or an organic group.
  • n is an integer of 1 to 5. When n is 2 or more, R 1 may be the same group or different groups. ) It is a compound shown by these.
  • aniline compound any reagent or industrial raw material can be used without any limitation.
  • the aniline compound represented by the formula (1) is a functional group such as a hydroxyl group or a cyano group even if R 1 is an atom such as a hydrogen atom or a halogen atom. May be. Furthermore, R 1 may be an organic group.
  • R1 is an organic group
  • the organic group is not particularly limited.
  • the organic group of R 1 is represented by an alkyl group or the following formula (4).
  • a group having an ether bond is preferred.
  • R 4 is preferably an alkyl group, an aryl group, or a group represented by the following formula (5) or the following formula (6).
  • R 5 and R 6 are each a hydrogen atom or an alkyl group.
  • m is an integer of 1 to 3.
  • R 7 and R 8 are each a hydrogen atom or an alkyl group.
  • the group R 1 in the aniline compound represented by the formula (1) is an alkyl group, considering the reactivity and the usefulness of the resulting carbonyloxy compound, the group R 1 is an alkyl having 1 to 6 carbon atoms. It is preferably a group.
  • the alkyl group When the group R 1 is an alkyl group, specific examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, an isopentyl group, and a hexyl group. Group or a cyclohexyl group.
  • the alkyl group may have 1 to 6 carbon atoms.
  • Alkyl groups are preferred. Specific examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, pentyl group, isopentyl group, hexyl group, and cyclohexyl group.
  • R 1 in the aniline compound represented by the formula (1) is a group represented by the formula (4) and R 4 is an aryl group
  • examples of the aryl group include a phenyl group or benzyl Groups and the like.
  • the group R 1 in the aniline compound represented by the formula (1) is a group represented by the formula (4) and R 4 is a group represented by the formula (5)
  • the group R 5 , and The groups R 6 are each a hydrogen atom or an alkyl group.
  • m is an integer of 1 to 3.
  • the alkyl group is preferably an alkyl group having 1 to 6 carbon atoms, and specific examples thereof include the same groups as the alkyl groups described for the group R 1. .
  • the group R 1 in the aniline compound represented by the formula (1) is a group represented by the above formula (4) and R 4 is a group represented by the above formula (6)
  • the group R 7 , and the group R 8 is each a hydrogen atom or an alkyl group.
  • the alkyl group an alkyl group having 1 to 6 carbon atoms is preferable, and specific examples thereof include the same groups as those described for the group R 1 .
  • n is an integer of 1 to 5, and represents the number of the group R 1 .
  • each group R 1 may be a different group or the same group.
  • n is preferably 1 to 2.
  • aniline compound represented by the above formula (1) Specific examples of the aniline compound represented by the above formula (1) are shown below. However, the present invention is not limited to the case where these aniline compounds are used as raw materials.
  • the above aniline compound is employed, and in the carbonyloxy compound synthesis step, the presence of a specific amine in the reaction system suppresses the formation of by-products, and the high purity and high purity carbonyloxy compound is obtained. Obtainable.
  • the production method of the present invention can be suitably employed for the production of a carbonyloxy compound that is an intermediate of a drug substance.
  • the aniline compound is 4- [2- (5-ethyl-2-pyridyl) ethoxy] aniline, the drug substance can be produced more efficiently.
  • Hydrogen bromide or hydrogen chloride can be used without any limitation as a reagent or industrial raw material.
  • Hydrogen chloride or hydrogen bromide is preferably hydrochloric acid or hydrobromic acid in an aqueous solution from the viewpoint of easy handling (hereinafter, hydrochloric acid and hydrobromic acid are collectively referred to as “acid”. May be displayed.)
  • hydrochloric acid and hydrobromic acid are collectively referred to as “acid”. May be displayed.
  • hydrobromic acid it is preferable to use general-purpose hydrobromic acid having a hydrogen bromide concentration of about 47% by mass.
  • the amount of acid used is twice the molar amount of the aniline compound. Therefore, the amount of acid used is preferably 2 mol or more of hydrogen chloride or hydrogen bromide with respect to 1 mol of the aniline compound.
  • the group R 1 of the aniline compound of the formula (1) is a functional group that forms a salt with an acid, it is preferable to increase the amount of acid used in consideration of the amount of the salt.
  • the group R 1 is a basic group such as a pyridyl group and forms a salt with an acid
  • the amount of acid used is increased according to the number of groups R 1 .
  • the preferred amount of hydrogen chloride or hydrogen bromide to be used is 3 to 5 moles.
  • the production method of the present invention can be suitably applied to a method for producing a carbonyloxy compound that is an intermediate of a drug substance.
  • a method for producing a carbonyloxy compound that is an intermediate of a drug substance When 4- [2- (5-ethyl-2-pyridyl) ethoxy] aniline is used as the aniline compound, the acid used is an odor in view of the good yield of the carbonyloxy compound obtained. Hydrohydric acid is preferred.
  • nitrite As the nitrite used in the present invention, reagents or industrial raw materials can be used without any limitation. Examples of the nitrite include sodium nitrite and potassium nitrite.
  • the amount of nitrite used is preferably 1 mol or more per 1 mol of the aniline compound.
  • the amount of nitrite used is more preferably 1 to 5 mol, further preferably 1 to 3 mol, and more preferably 1 to 2 mol, relative to 1 mol of the aniline compound. It is particularly preferable that
  • Nitrite may be added directly to the reaction solution as it is in the solid state. However, in general, it is preferable to add an aqueous solution of nitrite dropwise to the reaction solution. In this case, considering the solubility and economy of nitrite, the amount of water in which nitrite is dissolved is preferably 1 to 3 ml, more preferably 1.2 to 2.5 ml, with respect to 1 g of nitrite.
  • the conditions for synthesizing the diazonium salt in the diazonium salt synthesis step are determined in consideration of improvement of the reaction rate, adjustment of the reaction temperature, reduction of side reaction products, and the like.
  • the synthesis reaction is preferably carried out in an organic solvent.
  • the organic solvent is preferably compatible with water. Specific examples include ketones such as acetone and methyl ethyl ketone, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, and nitriles such as acetonitrile.
  • ketones such as acetone and methyl ethyl ketone
  • alcohols such as methanol and ethanol
  • ethers such as tetrahydrofuran
  • nitriles such as acetonitrile.
  • reagents or solvents for industrial raw materials can be used without any limitation.
  • a solvent can also be used individually or in mixture of 2 or more types.
  • the solubility of the raw material As the solvent for increasing the reaction rate, the solubility of the raw material, the solubility of the obtained diazonium salt, and the selectivity of the obtained diazonium salt, ketones and alcohols are preferable. Moreover, these mixed solvents are also preferable.
  • the amount of the organic solvent or mixed solvent used is preferably 5 to 25 ml, more preferably 7 to 20 ml, with respect to 1 g of the aniline compound used in consideration of economy and reduction of side reaction products.
  • the mixing method and order of addition of hydrogen chloride or hydrogen bromide, the aniline compound represented by the formula (1), and the nitrite there is no particular limitation on the mixing method and order of addition of hydrogen chloride or hydrogen bromide, the aniline compound represented by the formula (1), and the nitrite.
  • the acid, aniline compound, and nitrite may be simultaneously introduced into the reaction vessel and mixed.
  • the following mixing method is preferable. That is, it is a method in which nitrite is added to a mixed solution obtained by mixing the aniline compound and acid dissolved or dispersed in an organic solvent as necessary. Nitrite is preferably added in the form of an aqueous solution.
  • the reaction temperature is preferably 0 to 15 ° C, more preferably 0 to 10 ° C. When the reaction temperature exceeds 15 ° C., side reactions tend to occur.
  • the reaction solution is preferably stirred.
  • the reaction time is not particularly limited. The reaction time is preferably 0.01 to 10 hours, more preferably 0.1 to 5 hours with stirring.
  • a diazonium salt corresponding to the raw material aniline compound is produced by performing the reaction according to the above reaction conditions.
  • the resulting diazonium salt is reacted with an ⁇ , ⁇ -unsaturated carbonyloxy compound in the subsequent carbonyloxy compound synthesis step.
  • the diazonium salt obtained may be purified before reacting with the ⁇ , ⁇ -unsaturated carbonyloxy compound in the next step.
  • the diazonium salt is an unstable compound. Therefore, it is preferable to use the obtained diazonium salt as it is for the next carbonyloxy compound synthesis step without purifying the diazonium compound.
  • the solution (reaction product solution) containing the diazonium salt produced according to the above-mentioned method without purification.
  • the solution (reaction product liquid) contains an organic solvent.
  • Carbonyloxy compound synthesis step comprises reacting the diazonium salt obtained in the diazonium salt synthesis step with the ⁇ , ⁇ -unsaturated carbonyloxy compound represented by the formula (2) in the presence of a copper catalyst. In this step, the carbonyloxy compound represented by the formula (3) is synthesized.
  • the greatest feature of the present invention which will be described in detail below, is that, in this step, a base having an acid dissociation index (pKa) at 25 ° C. of 7 or less is present in the reaction system.
  • R 2 is a hydrogen atom, an alkyl group, an alkenyl group or an aryl group.
  • R 3 is a hydrogen atom, an alkyl group, or an aryl group.
  • the alkyl group is preferably an alkyl group having 1 to 6 carbon atoms.
  • the alkyl group has 1 to 6 carbon atoms, the reactivity is high and the usefulness of the resulting carbonyloxy compound is high.
  • Specific examples of preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, and cyclohexyl groups. .
  • examples of the alkenyl group include an allyl group having 2 to 6 carbon atoms and a vinyl group.
  • the group R 2 is an aryl group
  • examples of the aryl group include a phenyl group having 6 to 12 carbon atoms, a benzyl group, and the like.
  • the group R 3 is an alkyl group or an aryl group
  • examples of the alkyl group or aryl group include the same groups as those exemplified for the group R 2 .
  • any reagent or industrial raw material can be used without any limitation.
  • the ⁇ , ⁇ -unsaturated carbonyloxy compound is determined according to the carbonyloxy compound to be synthesized.
  • ⁇ , ⁇ -unsaturated carbonyloxy compounds include acrylic acid, methyl acrylate, acrylic acid Ethyl, butyl acrylate, isobutyl acrylate, t-butyl acrylate, methacrylic acid, methyl methacrylate, ethyl methacrylate, butyl methacrylate, isobutyl methacrylate, t-butyl methacrylate, allyl methacrylate, vinyl methacrylate, methacryl Preference is given to benzyl acid, cinnamic acid, methyl cinnamate, ethyl cinnamate, benzyl cinnamate, vinyl cinnamate and the like.
  • methyl acrylate or ethyl acrylate is preferable as the ⁇ , ⁇ -unsaturated carbonyloxy compound. Further, when importance is attached to the ease of purification of the obtained carbonyloxy compound, methyl acrylate is preferred as the ⁇ , ⁇ -unsaturated carbonyloxy compound.
  • the amount of the ⁇ , ⁇ -unsaturated carbonyloxy compound represented by the formula (2) is preferably 1 mol or more and more preferably 2 mol or more with respect to 1 mol of the diazonium salt used in the reaction. When the amount is less than 1 mol, the yield decreases.
  • the upper limit of the amount of ⁇ , ⁇ -unsaturated carbonyloxy compound used is not particularly limited, but considering the operability and economic efficiency of post-treatment after the reaction, a diazonium salt derived from an aniline compound 50 mol is preferable with respect to 1 mol, and 40 mol is more preferable.
  • copper catalyst As the copper catalyst used in the carbonyloxy compound synthesis step, any reagent or industrial raw material can be used without any limitation.
  • the copper catalyst that can be used include copper (I) oxide, copper (II) oxide, copper (I) bromide, copper (II) bromide and the like.
  • the amount of copper catalyst used is the same as the usual amount of catalyst. Specifically, the amount is preferably 0.01 to 0.2 mol, more preferably 0.02 to 0.1 mol, with respect to 1 mol of the diazonium salt derived from the aniline compound. When the amount is less than 0.01 mol, the reaction time tends to be long. When it exceeds 0.2 mol, it becomes difficult to shorten the reaction time in proportion to the amount of copper catalyst used.
  • Base having an acid dissociation index (pKa) at 25 ° C. of 7 or less The greatest feature of the present invention is that in this carbonyloxy compound synthesis step, a base having an acid dissociation index (pKa) at 25 ° C. of 7 or less is present in the reaction system. Even when a base having an acid dissociation index (pKa) at 25 ° C. of 7 or less is not present in the reaction system, the reaction for synthesizing the carbonyloxy compound proceeds. However, when a base having an acid dissociation index (pKa) at 25 ° C. of 7 or less is present, a high-purity carbonyloxy compound represented by the formula (3) can be obtained in a high yield.
  • the lower limit of the acid dissociation index (pKa) at 25 ° C. of the base that can be used is 4 considering the availability of the base.
  • a reagent or a base for industrial raw materials can be used without any limitation.
  • the value described in parentheses indicates an acid dissociation index at 25 ° C.
  • the base to be present in the reaction system is particularly preferably a nitrogen-containing heterocyclic compound having an acid dissociation index (pKa) at 25 ° C. of 4 or more and 7 or less.
  • the nitrogen-containing heterocyclic compound refers to a heterocyclic compound containing at least one nitrogen atom in the heterocyclic ring.
  • nitrogen-containing heterocyclic compounds examples include pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2,4-dimethylpyridine, 2,6-dimethylpyridine, 2,2′-bipyridyl, 4 , 4′-bipyridyl, 1,10-phenanthroline, 1-methylimidazole and the like.
  • a compound having a pyridine ring is particularly preferable in view of the selectivity of the reaction and ease of operability.
  • Specific examples include pyridine compounds such as pyridine and 2-methylpyridine, and bipyridyl compounds such as 2,2'-bipyridyl and 4,4'-bipyridyl.
  • the amount of the base used is preferably 0.05 to 10 mol, more preferably 0.1 to 5 mol, per 1 mol of the diazonium salt derived from the aniline compound. Within the range of the use amount of the base, preferable effects such as reaction selectivity, yield, purity improvement, operability improvement, economy and the like are exhibited.
  • the above effect is exhibited by the presence of a base having an acid dissociation index (pKa) at 25 ° C. of 7 or less. The reason for this has not been elucidated.
  • the present inventors considered that a base having an acid dissociation index (pKa) at 25 ° C. of 7 or less interacts with the copper catalyst to suppress the Sandmeyer reaction, which is a side reaction of the Meerwein arylation reaction. Yes.
  • reaction conditions other than the above are not particularly limited. There are no particular limitations on the method of adding each component and the method of mixing in the carbonyloxy compound synthesis step.
  • the reaction proceeds by mixing the ⁇ , ⁇ -unsaturated carbonyloxy compound and the base with the solution containing the diazonium salt, and further adding and mixing the copper catalyst.
  • the reaction proceeds by adding a solution containing a diazonium salt dropwise to the mixture of the ⁇ , ⁇ -unsaturated carbonyloxy compound and the base in the presence of a copper catalyst and mixing them.
  • the copper catalyst can be added to the mixture of the ⁇ , ⁇ -unsaturated carbonyloxy compound and the base simultaneously with the solution containing the diazonium salt. Furthermore, a copper catalyst can be added to the mixture in advance. In view of ease of reaction control, simplification of the apparatus, etc., it is preferable to previously mix a copper catalyst with the mixture of the ⁇ , ⁇ -unsaturated carbonyloxy compound and the base.
  • the reaction is carried out in the form of a mixture (mixture) of the ⁇ , ⁇ -unsaturated carbonyloxy compound and the base using an organic solvent. It is preferable to make it.
  • the ⁇ , ⁇ -unsaturated carbonyloxy compound is in a liquid state at the reaction temperature, the mixture is in the state of a mixture (mixture) of the ⁇ , ⁇ -unsaturated carbonyloxy compound and the base without using an organic solvent. You may make it react.
  • the reaction temperature is preferably 10 to 60 ° C, more preferably 15 to 50 ° C.
  • the reaction time is not particularly limited. What is necessary is just to determine suitably, confirming the progress of reaction. In general, when the reaction time is controlled within the above temperature range, 0.1 to 10 hours are preferable, and 0.5 to 5 hours are more preferable. It is preferable to stir during the reaction.
  • the reaction product solution is obtained by reacting under the reaction conditions of the carbonyloxy compound synthesis step.
  • the resulting reaction product solution is neutralized with an alkaline aqueous solution such as aqueous ammonia according to a conventional method, and then subjected to an extraction treatment using a solvent such as ethyl acetate.
  • the extraction solvent is separated from the reaction product solution.
  • the carbonyloxy compound shown by following formula (3) can be obtained by distilling an extraction solvent off.
  • the carbonyloxy compound represented by the above formula (3) thus obtained may be further purified by a known method such as crystallization, distillation, column purification or the like according to the intended use.
  • a carbonyloxy compound represented by the following formula (3) can be synthesized by performing each reaction of the diazonium salt synthesis step and the carbonyloxy compound synthesis step.
  • R 1 and n have the same meaning as in formula (1), R 2 and R 3 have the same meaning as in the formula (2), X is a chlorine atom or a bromine atom.
  • the groups R 1 , R 2 , and R 3 are functional groups determined according to the aniline compound and the ⁇ , ⁇ -unsaturated carbonyloxy compound to be used.
  • the group X is a functional group determined according to the acid used (hydrogen chloride (hydrochloric acid) or hydrogen bromide (hydrobromic acid)).
  • the production method of 5- ⁇ 4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl ⁇ -2-imino-4-thiazolidinone represented by the formula (12) is a known method.
  • the method described in Patent Document 1 can be used.
  • an organic solvent such as ethanol is used as a reaction solvent, and a compound represented by the formula (11) is reacted with thiourea in the presence of an alkali to give a 5- ⁇ 4- [2- (5-Ethyl-2-pyridyl) ethoxy] benzyl ⁇ -2-imino-4-thiazolidinone can be efficiently produced.
  • alkali examples include lithium acetate, sodium acetate, potassium acetate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, tert-butoxy potassium, sodium hydride, sodium methoxide, sodium ethoxide, Lithium hydroxide, sodium hydroxide, potassium hydroxide and the like are preferable.
  • the amount of alkali used is preferably 1 to 3 mol per 1 mol of the compound represented by the formula (11).
  • the amount of thiourea used is preferably 1 to 3 moles relative to 1 mole of the compound represented by the formula (11).
  • the reaction temperature is preferably 25 to 120 ° C., and the reaction time is preferably 1 to 50 hours.
  • the addition method of alkali and thiourea is not particularly limited, and all components may be mixed and reacted at the reaction temperature for the above time.
  • the reaction solution is cooled to give 5- ⁇ 4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl ⁇ -represented by the formula (12). Crystals of 2-imino-4-thiazolidinone are precipitated. Furthermore, in order to improve the yield, the reaction solution is concentrated under reduced pressure, and the resulting residue is neutralized with a saturated aqueous sodium carbonate solution, and then added with water and ether, and cooled to obtain the formula (12). Crystals of the compound shown are obtained. This crystal can be purified by a usual method. For example, it can be purified by a method of washing with water and drying. The resulting compound represented by the formula (12) can be used in the next reaction.
  • the compound of the formula (11) obtained by the production method of the present invention has a high purity and a high yield. Therefore, in comparison with the conventional method, when the compound of the formula (11) obtained by the method of the present invention is used, the compound represented by the formula (12) can be obtained in a high yield.
  • Example 1 (Diazonium salt synthesis process) 0.47 g (5 mmol) of aniline was dissolved in 4.6 ml of methanol and 5.7 ml of acetone, cooled to 10 ° C., and 1.76 g of 47% by mass of hydrobromic acid (10.2 mmol of hydrogen bromide) was added. The solution containing aniline and hydrobromic acid was cooled to 2 ° C. While keeping the solution containing aniline and hydrobromic acid not exceeding 5 ° C., an aqueous nitrous acid solution was added dropwise to the stirring solution. The aqueous nitrous acid solution was prepared by dissolving 0.35 g (5.7 mmol) of sodium nitrite in 0.7 ml of water. A nitrous acid aqueous solution was added dropwise, and the mixture was stirred at 3 ° C. for 20 minutes to synthesize a diazonium salt.
  • the diazonium salt was subjected to the next reaction without being purified and contained in the solution.
  • the purity of the diazonium salt was confirmed by HPLC (high performance liquid chromatography)
  • the purity was 99.0% by mass
  • the diazonium salt was quantitatively synthesized. That is, almost the entire amount of aniline was a diazonium salt.
  • Examples 2 to 6 In the diazonium salt synthesis step of Example 1, the same operation as in Example 1 was performed except that the aniline compound shown in Table 1 was used instead of aniline. The results are shown in Table 1.
  • the diazonium salt obtained in the diazonium salt synthesis step of each example had a purity of 99.0% by mass or more. Therefore, the diazonium salt has been synthesized quantitatively.
  • Examples 12-14 In the carbonyloxy compound synthesis step of Example 1, an experiment similar to Example 1 was performed, except that the compound shown in Table 3 ( ⁇ , ⁇ -unsaturated carbonyloxy compound) was used instead of methyl acrylate. . The results are shown in Table 3.
  • Comparative Example 1 The same operation as in Example 1 was performed except that pyridine was not added in Example 1. As a result, 1.07 g (yield 52.8%) of methyl 2-bromo-3-phenylpropionate having an HPLC purity of 60.0% by mass was obtained.
  • Example 20 (Production of 5- ⁇ 4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl ⁇ -2-imino-4-thiazolidinone) 1.73 g (purity: 82.1%) of methyl 2-bromo-3- ⁇ 4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl ⁇ propionate obtained in Example 5 was added to a Dimroth reflux tube. A three-necked flask equipped with a thermometer was charged.
  • Example 21 (Production of 5- ⁇ 4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl ⁇ thiazolidine-2,4-dione hydrochloride) 3- ⁇ 4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl ⁇ -2-imino-4-thiazolidinone 1.16 g obtained in Example 20 was equipped with a Dimroth reflux tube and a thermometer. 9.8 mL of 1.0 mol / L hydrochloric acid aqueous solution was added to the necked flask and dissolved at room temperature.
  • Comparative Example 8 (Production of 5- ⁇ 4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl ⁇ -2-imino-4-thiazolidinone) 1.67 g (purity 59.6%) of methyl 2-bromo-3- ⁇ 4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl ⁇ propionate obtained in Comparative Example 5 was added to a Dimroth reflux tube. A three-necked flask equipped with a thermometer was charged.
  • Comparative Example 9 (Production of 5- ⁇ 4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl ⁇ thiazolidine-2,4-dione hydrochloride)
  • a 0.80 g of 5- ⁇ 4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl ⁇ -2-imino-4-thiazolidinone obtained in Comparative Example 8 was equipped with a Dimroth reflux tube and a thermometer. The mixture was charged into a one-necked flask, and 6.7 mL of a 1.0 mol / L hydrochloric acid aqueous solution was added and dissolved at room temperature.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention a pour objet un procédé de production d’un composé carbonyloxy qui comprend la réaction d’un composé d’aniline avec un sel de l’acide nitreux en présence d’un acide pour synthétiser un sel de diazonium et ensuite la réaction du sel de diazonium avec un composé carbonyloxy α,β-insaturé en présence d’un catalyseur de cuivre pour produire le composé carbonyloxy souhaité. Ce procédé est caractérisé en ce que la réaction entre le sel de diazonium et le composé carbonyloxy α,β-insaturé est conduite en présence d’une base présentant une constante de dissociation acide (pKa) à 25º C de 7 ou inférieure. Selon le procédé, du 2-bromo-3-{4-[2-(5-éthyl-2-pyridyl)- éthoxy]phényl}propionate de méthyle est employé en tant qu’intermédiaire pour un agent thérapeutique qui produit un excellent effet sur le diabète de type 2 qui est provoqué par une déficience de l’action de l’insuline et d’autres composés qui peuvent être obtenus d’une manière hautement efficace de façon à présenter une pureté élevée.
PCT/JP2009/066022 2008-10-10 2009-09-14 Procédé de production d’un composé carbonyloxy WO2010041538A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012118216A1 (fr) 2011-02-28 2012-09-07 独立行政法人理化学研究所 Inhibiteur de biosynthèse de l'auxine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6081143A (ja) * 1983-10-13 1985-05-09 Toyo Soda Mfg Co Ltd ハロゲン含有エチルベンゼン誘導体の製造方法
JPS61267580A (ja) * 1985-01-19 1986-11-27 Takeda Chem Ind Ltd チアゾリジン誘導体
JPH07233120A (ja) * 1993-10-20 1995-09-05 Hoechst Ag ３−（ｐ−フルオロフェニル）−２−メチルプロピオン酸および３−（ｐ−フルオロフェニル）−２−メチルプロピオン酸誘導体の製造方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0780378B1 (fr) * 1995-12-19 2003-04-09 Bayer CropScience S.A. Nouveau dérivés de 1-aryl pyrazole et leur utilisation comme pesticides
KR20020016804A (ko) * 1999-05-26 2002-03-06 미우라 아키라 6-히드록시-2-나프틸카르비놀 및 그의 제조방법

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6081143A (ja) * 1983-10-13 1985-05-09 Toyo Soda Mfg Co Ltd ハロゲン含有エチルベンゼン誘導体の製造方法
JPS61267580A (ja) * 1985-01-19 1986-11-27 Takeda Chem Ind Ltd チアゾリジン誘導体
JPH07233120A (ja) * 1993-10-20 1995-09-05 Hoechst Ag ３−（ｐ−フルオロフェニル）−２−メチルプロピオン酸および３−（ｐ−フルオロフェニル）−２−メチルプロピオン酸誘導体の製造方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SOHDA, T. ET AL.: "Studies on Antidiabetic Agents. II. Synthesis of 5-[4-(1- Methylcyclohexylmethoxy)-benzyl]thiazolidine-2, 4-dione (ADD-3878) and Its Derivatives", CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 30, no. 10, 1982, pages 3580 - 3600 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012118216A1 (fr) 2011-02-28 2012-09-07 独立行政法人理化学研究所 Inhibiteur de biosynthèse de l'auxine

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