WO2010041538A1 - カルボニルオキシ化合物の製造方法 - Google Patents
カルボニルオキシ化合物の製造方法 Download PDFInfo
- Publication number
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- group
- carbonyloxy
- ethyl
- formula
- Prior art date
Links
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Nc1ccccc1 Chemical compound Nc1ccccc1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
ジャーナル・オブ・メディシナル・ケミストリー35巻、14号、2617-2626(1992)
塩化水素、または臭化水素の存在下、
下記式(1)
R1は、水素原子、ハロゲン原子、ヒドロキシル基、シアノ基、または有機基である。nは1~5の整数である。nが2以上である場合には、R1は、同一の基であっても異なる基であってもよい。)
で示されるアニリン化合物と亜硝酸塩とを反応させて、ジアゾニウム塩を合成するジアゾニウム塩合成工程、および
銅触媒の存在下、該ジアゾニウム塩合成工程で得られるジアゾニウム塩と、下記式(2)
R2は、水素原子、アルキル基、アルケニル基またはアリール基である。
で示されるα,β-不飽和カルボニルオキシ化合物と、を反応させて、下記式(3)
R1、およびnは、前記式(1)におけるものと同義であり、
R2、およびR3は、前記式(2)におけるものと同義であり、
Xは、塩素原子、または臭素原子である。)
で示されるカルボニルオキシ化合物を合成するカルボニルオキシ化合物合成工程、
を含むカルボニルオキシ化合物の製造方法であって、
前記カルボニルオキシ化合物合成工程において、ジアゾニウム塩とα,β-不飽和カルボニルオキシ化合物とを反応させる際に、反応系に25℃における酸解離指数(pKa)が7以下の塩基を存在させることを特徴とするカルボニルオキシ化合物の製造方法である。
ジアゾニウム塩合成工程は、塩化水素、または臭化水素の存在下、前記式(1)で示されるアニリン化合物と亜硝酸塩とを反応させて、該アニリン化合物に由来するジアゾニウム塩を合成する工程である。
前記ジアゾニウム塩合成工程において、原料となるアニリン化合物は、下記式(1)
R1は、水素原子、ハロゲン原子、ヒドロキシル基、シアノ基、または有機基である。nは1~5の整数である。nが2以上である場合には、R1は、同一の基であっても異なる基であってもよい。)
で示される化合物である。
R4は、アルキル基、アリール基、下記式(5)又は下記式(6)で示される基が好ましい。
R5、およびR6は、それぞれ、水素原子、またはアルキル基である。mは1~3の整数である。)
R7、およびR8は、それぞれ、水素原子、またはアルキル基である。)
式(1)で示されるアニリン化合物中の基R1がアルキル基である場合、反応性、および得られるカルボニルオキシ化合物の有用性等を考慮すると、基R1は、炭素数1~6のアルキル基であることが好ましい。基R1がアルキル基である場合、アルキル基としては、具体的には、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、t-ブチル基、ペンチル基、イソペンチル基、ヘキシル基、またはシクロヘキシル基等が挙げられる。
ジアゾニウム塩合成工程においては、塩化水素、または臭化水素の存在下、前記アニリン化合物と亜硝酸塩とを反応させて、前記アニリン化合物に由来するジアゾニウム塩を合成する。
本発明で使用される亜硝酸塩は、試薬あるいは工業原料が何ら制限なく使用できる。亜硝酸塩としては、亜硝酸ナトリウム、亜硝酸カリウム等が例示される。
ジアゾニウム塩合成工程におけるジアゾニウム塩の合成条件は、反応速度の向上、反応温度の調整、副反応物の低減等を考慮して決定する。合成反応は、有機溶媒中で実施することが好ましい。有機溶媒は、水と相溶するものが好ましい。具体的には、アセトン、メチルエチルケトンなどのケトン類、メタノール、エタノールなどのアルコール類、テトラヒドロフランなどのエーテル類、アセトニトリルなどのニトリル類が挙げられる。これらの有機溶媒は、試薬或いは工業原料用溶媒が何ら制限無く使用できる。溶媒は、単独で、または2種類以上を混合して使用することもできる。反応速度、原料の溶解度、得られるジアゾニウム塩の溶解度、得られるジアゾニウム塩の選択率が高くなる溶媒としてはケトン類、アルコール類が好ましい。また、これらの混合溶媒も好ましい。
カルボニルオキシ化合物合成工程は、銅触媒存在下、該ジアゾニウム塩合成工程で得られるジアゾニウム塩と、前記式(2)で示されるα,β-不飽和カルボニルオキシ化合物とを反応させて、前記式(3)で示されるカルボニルオキシ化合物を合成する工程である。本発明の最大の特徴は、下記に詳述するが、この工程において、反応系に25℃における酸解離指数(pKa)が7以下の塩基を存在させることである。
本発明において、前記ジアゾニウム塩と反応させるα,β-不飽和カルボニルオキシ化合物は、下記式(2)
R2は、水素原子、アルキル基、アルケニル基またはアリール基である。
で示される。
カルボニルオキシ化合物合成工程において使用する銅触媒は、試薬或いは工業原料が何ら制限無く使用できる。使用できる銅触媒を例示すると、酸化銅(I)、酸化銅(II)、臭化銅(I)、臭化銅(II)などが挙げられる。銅触媒の使用量は、通常の触媒量と同じである。具体的には、アニリン化合物由来のジアゾニウム塩1モルに対して、0.01~0.2モルが好ましく、0.02~0.1モルがより好ましい。0.01モル未満の場合は、反応時間が長くなる傾向がある。0.2モルを超える場合は、使用する銅触媒量に比例して反応時間が短縮し難くなる。
本発明の最大の特徴は、このカルボニルオキシ化合物合成工程において、反応系に、25℃における酸解離指数(pKa)が7以下の塩基を存在させることである。25℃における酸解離指数(pKa)が7以下の塩基を反応系に存在させない場合でも、カルボニルオキシ化合物を合成する反応は進行する。しかし、25℃における酸解離指数(pKa)が7以下の塩基を存在させることにより、式(3)で示される高純度のカルボニルオキシ化合物が高収率で得られる。
カルボニルオキシ化合物合成工程において、上記以外の反応条件は、特に制限が無い。カルボニルオキシ化合物合成工程における各成分の添加方法、および混合方法も特に制限がない。
本発明においては、前記ジアゾニウム塩合成工程、カルボニルオキシ化合物合成工程の各反応を行うことにより、下記式(3)で示されるカルボニルオキシ化合物を合成することができる。
R1、およびnは、前記式(1)におけるものと同義であり、
R2、およびR3は、前記式(2)におけるものと同義であり、
Xは、塩素原子、または臭素原子である。)
なお、前記式(3)において、基R1、R2、およびR3は、使用するアニリン化合物、およびα,β-不飽和カルボニルオキシ化合物に応じて定まる官能基である。
本発明の製造方法によれば、高純度のカルボニルオキシ化合物を高収率で製造することができる。本発明の製造方法により、式(3)で示されるカルボニルオキシ化合物として、下記式(11)で示される2-ブロモ-3-{4-[2-(5-エチル-2-ピリジル)エトキシ]フェニル}プロピオン酸メチルを製造する場合には、式(11)で示される化合物を高純度、高収率で得ることができる。
上記の通り、本発明の式(12)で示される化合物の製造方法は、高収率で、不純物の含有量が少ない。その結果、この式(12)の化合物を原料として使用することにより、式(13)で示される5-{4-[2-(5-エチル-2-ピリジル)エトキシ]ベンジル}チアゾリジン-2,4-ジオン塩酸塩を高収率で得ることができる。
(ジアゾニウム塩合成工程)
アニリン0.47g(5mmol)をメタノール4.6ml、アセトン5.7mlに溶解させ、10℃まで冷却し、47質量%の臭化水素酸1.76g(臭化水素10.2mmol)を加えた。このアニリンと臭化水素酸を含む溶液を2℃まで冷却した。アニリンと臭化水素酸を含む溶液が5℃を超えないように保ちながら、撹拌中の該溶液に亜硝酸水溶液を滴下した。前記亜硝酸水溶液は水0.7mlに亜硝酸ナトリウム0.35g(5.7mmol)を溶解させて調製したものである。亜硝酸水溶液を滴下後、3℃で、20分間撹拌して、ジアゾニウム塩を合成した。
別の容器に、アクリル酸メチル5.14g(10mmol)、ピリジン1.19g(15mmol、25℃の酸解離指数(pKa)=5.42)、臭化銅(I)0.091g(0.63mmol)を加え、47℃まで昇温した。その後、47℃に加熱した、アクリル酸メチルとピリジンと臭化銅(I)とを含む混合液を撹拌しながら、該混合液中に、前記ジアゾニウム塩合成工程で製造したジアゾニウム塩を含む溶液を30分かけて滴下した。滴下後、反応液をさらに47℃で2時間撹拌した後、溶媒を留去した。得られた残留物に、酢酸エチル20ml、28質量%アンモニア水10mlを加えた。分液した有機層を水洗し、乾燥した。その後、有機層の溶媒を留去した。その結果、カルボニルオキシ化合物として、2-ブロモ-3-フェニルプロピオン酸メチル1.08gを得た。HPLCにより純度を確認したところ、純度は81.2質量%であった。よって、2-ブロモ-3-フェニルプロピオン酸メチルの収率は72.3%であった。
実施例1のジアゾニウム塩合成工程において、アニリンに代えて表1に示したアニリン化合物を使用した以外は、実施例1と同様の操作を行った。その結果を表1に示した。なお、各実施例のジアゾニウム塩合成工程において得られたジアゾニウム塩は、純度が99.0質量%以上であった。従って、ジアゾニウム塩は定量的に合成されていた。
実施例1のカルボニルオキシ化合物合成工程において、ピリジンに代えて2,2’-ビピリジル(25℃の酸解離指数(pKa)=4.42)を表2に示したアニリン化合物に対して1.5倍モル当量(ジアゾニウム塩1モルに対して、1.5モルの2,2’-ビピリジルに相当する量)使用した以外は、実施例1と同様の操作を行った。その結果を表2に示した。
実施例1のカルボニルオキシ化合物合成工程において、アクリル酸メチルに代えて表3に示した化合物(α,β-不飽和カルボニルオキシ化合物)を使用した以外は、実施例1と同様の実験を行った。その結果を表3に示した。
実施例1において、ピリジンを加えなかった以外は、実施例1と同様の操作を行った。その結果、HPLC純度60.0質量%の2-ブロモ-3-フェニルプロピオン酸メチル1.07g(収率52.8%)を得た。
実施例2~6において、ピリジンを加えなかった以外は、実施例2~6と同様の操作を行った。その結果を表4に示した。
実施例5において、ピリジンに代えてトリエチルアミン(25℃における酸解離指数(pKa)=10.72)を使用した以外は、実施例5と同様の操作を行った。その結果、HPLC純度12.7質量%の2-ブロモ-3-{4-[2-(5-エチル-2-ピリジル)エトキシ]フェニル}プロピオン酸メチルを1.68g(収率10.9%)得た。
実施例1のカルボニルオキシ化合物合成工程において、ピリジンに代えて1-メチルイミダゾール(25℃の酸解離指数(pKa)=6.95)を表5に示したアニリン化合物に対して使用した以外は、実施例1と同様の操作を行った。その結果を表5に示した。
実施例5で得られた2-ブロモ-3-{4-[2-(5-エチル-2-ピリジル)エトキシ]フェニル}プロピオン酸メチル1.73g(純度82.1%)をジムロート還流管と温度計を備えた3つ口フラスコに仕込んだ。次いで、エタノール9ml、チオ尿素0.55gを加えて2-ブロモ-3-{4-[2-(5-エチル-2-ピリジル)エトキシ]フェニル}プロピオン酸メチルを溶解させた後、撹拌下、酢酸ナトリウム0.59gを加えて4時間還流した。還流後、冷却すると結晶が析出した。析出した結晶をろ過し、水洗し、乾燥させることにより、5-{4-[2-(5-エチル-2-ピリジル)エトキシ]ベンジル}-2-イミノ-4-チアゾリジノンの微黄色結晶1.16g(収率90.1%、アニリン化合物からの全収率65.2%)を得た。HPLCにより純度を確認したところ、純度は99.01質量%であった。
実施例20で得られた5-{4-[2-(5-エチル-2-ピリジル)エトキシ]ベンジル}-2-イミノ-4-チアゾリジノン1.16gをジムロート還流管と温度計を備えた3つ口フラスコに仕込み、1.0mol/L塩酸水溶液を9.8mL加え、室温で溶解させた。溶媒を還流させながら4時間攪拌を行い、5-{4-[2-(5-エチル-2-ピリジル)エトキシ]ベンジル}-2-イミノ-4-チアゾリジノンの加水分解を行った。反応後、得られた反応液を1.5時間かけて5℃まで冷却すると、結晶が析出した。得られた結晶をろ過し、真空下で12時間乾燥させ、(5-{4-[2-(5-エチル-2-ピリジル)エトキシ]ベンジル}チアゾリジン-2,4-ジオン塩酸塩の白色結晶1.16g(収率90.2%、アニリン化合物からの全収率58.8%)を得た。HPLCにより純度を確認したところ、純度は99.1質量%であった。
比較例5で得られた2-ブロモ-3-{4-[2-(5-エチル-2-ピリジル)エトキシ]フェニル}プロピオン酸メチル1.67g(純度59.6%)をジムロート還流管と温度計を備えた3つ口フラスコに仕込んだ。次いで、エタノール9ml、チオ尿素0.34gを加えて2-ブロモ-3-{4-[2-(5-エチル-2-ピリジル)エトキシ]フェニル}プロピオン酸メチルを溶解させた後、撹拌下、酢酸ナトリウム0.37gを加えて4時間還流した。還流後、冷却すると結晶が析出した。析出した結晶をろ過、水洗、乾燥を行い、5-{4-[2-(5-エチル-2-ピリジル)エトキシ]ベンジル}-2-イミノ-4-チアゾリジノンの微黄色結晶0.80g(収率88.7%、アニリン化合物からの全収率45.0%)を得た。HPLCにより純度を確認したところ、純度は98.98質量%であった。
比較例8で得られた5-{4-[2-(5-エチル-2-ピリジル)エトキシ]ベンジル}-2-イミノ-4-チアゾリジノン0.80gをジムロート還流管と温度計を備えた3つ口フラスコに仕込み、1.0mol/L塩酸水溶液を6.7mL加え、室温で溶解させた。溶媒を還流させながら4時間攪拌を行い、5-{4-[2-(5-エチル-2-ピリジル)エトキシ]ベンジル}-2-イミノ-4-チアゾリジノンの加水分解を行った。反応後、得られた反応液を1.5時間かけて5℃まで冷却すると、結晶が析出した。得られた結晶をろ過し、真空下で12時間乾燥させ、(5-{4-[2-(5-エチル-2-ピリジル)エトキシ]ベンジル}チアゾリジン-2,4-ジオン塩酸塩の白色結晶0.80g(収率90.5%、アニリン化合物からの全収率40.7%)を得た。HPLCにより純度を確認したところ、純度は99.12質量%であった。
Claims (7)
- 塩化水素、または臭化水素の存在下、
下記式(1)
R1は、水素原子、ハロゲン原子、ヒドロキシル基、シアノ基、または有機基である。nは1~5の整数である。nが2以上である場合には、R1は、同一の基であっても異なる基であってもよい。)
で示されるアニリン化合物と亜硝酸塩とを反応させて、ジアゾニウム塩を合成するジアゾニウム塩合成工程、および
銅触媒存在下、該ジアゾニウム塩合成工程で得られるジアゾニウム塩と下記式(2)
R2は、水素原子、アルキル基、アルケニル基またはアリール基である。
R3は、水素原子、アルキル基、またはアリール基である。)
で示されるα,β-不飽和カルボニルオキシ化合物とを反応させて、下記式(3)
R1、およびnは、前記式(1)におけるものと同義である。
R2、およびR3は、前記式(2)におけるものと同義である。
Xは、塩素原子、または臭素原子である。)
で示されるカルボニルオキシ化合物を合成するカルボニルオキシ化合物合成工程、
を含むカルボニルオキシ化合物の製造方法であって、
前記カルボニルオキシ化合物合成工程において、ジアゾニウム塩とα,β-不飽和カルボニルオキシ化合物とを反応させる際に、反応系に25℃における酸解離指数(pKa)が7以下の塩基を存在させることを特徴とするカルボニルオキシ化合物の製造方法。 - 前記カルボニルオキシ化合物合成工程において、ジアゾニウム塩1モルに対して、25℃の酸解離指数(pKa)が7以下の塩基を0.05~10モル使用する請求項1に記載のカルボニルオキシ化合物の製造方法。
- 前記カルボニルオキシ化合物合成工程において、25℃の酸解離指数(pKa)が7以下の塩基として、25℃の酸解離指数(pKa)が4~7の窒素含有複素環式化合物を使用する請求項1に記載のカルボニルオキシ化合物の製造方法。
- 前記ジアゾニウム塩合成工程において、臭化水素を使用し、前記式(1)で示されるアニリン化合物として4-[2-(5-エチル-2-ピリジル)エトキシ]アニリンを使用し、かつ、前記カルボニルオキシ化合物合成工程において、前記式(2)で示されるα,β-不飽和カルボニルオキシ化合物としてアクリル酸メチルを使用することにより、2-ブロモ-3-{4-[2-(5-エチル-2-ピリジル)エトキシ]フェニル}プロピオン酸メチルを製造することを特徴とする請求項1に記載のカルボニルオキシ化合物の製造方法。
- 請求項5に記載のカルボニルオキシ化合物の製造方法によって、2-ブロモ-3-{4-[2-(5-エチル-2-ピリジル)エトキシ]フェニル}プロピオン酸メチルを製造した後、アルカリ存在下、得られた2-ブロモ-3-{4-[2-(5-エチル-2-ピリジル)エトキシ]フェニル}プロピオン酸メチルとチオ尿素とを反応させることを特徴とする5-{4-[2-(5-エチル-2-ピリジル)エトキシ]ベンジル}-2-イミノ-4-チアゾリジノンの製造方法。
- 請求項6に記載の方法によって、5-{4-[2-(5-エチル-2-ピリジル)エトキシ]ベンジル}-2-イミノ-4-チアゾリジノンを製造した後、得られた5-{4-[2-(5-エチル-2-ピリジル)エトキシ]ベンジル}-2-イミノ-4-チアゾリジノンと塩化水素とを反応させることを特徴とする5-{4-[2-(5-エチル-2-ピリジル)エトキシ]ベンジル}チアゾリジン-2,4-ジオン塩酸塩の製造方法。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010532869A JP5441913B2 (ja) | 2008-10-10 | 2009-09-14 | カルボニルオキシ化合物の製造方法 |
CN2009801350565A CN102149669A (zh) | 2008-10-10 | 2009-09-14 | 羰氧基化合物的制备方法 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2008-263450 | 2008-10-10 | ||
JP2008263450 | 2008-10-10 | ||
JP2008-293181 | 2008-11-17 | ||
JP2008293181 | 2008-11-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010041538A1 true WO2010041538A1 (ja) | 2010-04-15 |
Family
ID=42100492
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2009/066022 WO2010041538A1 (ja) | 2008-10-10 | 2009-09-14 | カルボニルオキシ化合物の製造方法 |
Country Status (4)
Country | Link |
---|---|
JP (1) | JP5441913B2 (ja) |
KR (1) | KR20110068979A (ja) |
CN (1) | CN102149669A (ja) |
WO (1) | WO2010041538A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012118216A1 (ja) | 2011-02-28 | 2012-09-07 | 独立行政法人理化学研究所 | オーキシン生合成阻害剤 |
Citations (3)
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)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69627281T2 (de) * | 1995-12-19 | 2003-11-13 | Bayer Cropscience Sa | Neue 1-Aryl Pyrazol Derivate und ihre Verwendung als Schädlingsbekämpfungsmittel |
EP1186588A4 (en) * | 1999-05-26 | 2003-01-22 | Mitsubishi Chem Corp | 6-HYDROXY-2-NAPHTYLCARBINOL AND A METHOD FOR THE PRODUCTION THEREOF |
-
2009
- 2009-09-14 WO PCT/JP2009/066022 patent/WO2010041538A1/ja active Application Filing
- 2009-09-14 CN CN2009801350565A patent/CN102149669A/zh active Pending
- 2009-09-14 KR KR1020117004006A patent/KR20110068979A/ko active IP Right Grant
- 2009-09-14 JP JP2010532869A patent/JP5441913B2/ja not_active Expired - Fee Related
Patent Citations (3)
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)
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)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012118216A1 (ja) | 2011-02-28 | 2012-09-07 | 独立行政法人理化学研究所 | オーキシン生合成阻害剤 |
Also Published As
Publication number | Publication date |
---|---|
JP5441913B2 (ja) | 2014-03-12 |
CN102149669A (zh) | 2011-08-10 |
KR20110068979A (ko) | 2011-06-22 |
JPWO2010041538A1 (ja) | 2012-03-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7683178B2 (en) | Method for the synthesis of a benzimidazole compound | |
JP2018523662A (ja) | クロマノン誘導体の新規な製造方法 | |
WO2004009553A1 (ja) | 5−(2’−ピリジル)−2−ピリドン誘導体の製造方法 | |
JP5441913B2 (ja) | カルボニルオキシ化合物の製造方法 | |
CN108864084B (zh) | 一组阿哌沙班有关物质及其制备方法 | |
JP5197063B2 (ja) | 2−ブロモ−3−{4−[2−(5−エチル−2−ピリジル)エトキシ]フェニル}プロピオン酸メチルの製造方法 | |
CN104136422B (zh) | 化合物、化合物的制造方法、以及化合物的精制方法 | |
CN108586280B (zh) | 合成n′-[(2s,3s)-2-(苄氧基)戊-3-基]甲酰肼的方法 | |
JP5078211B2 (ja) | 複素環式化合物の製造方法 | |
JP5383123B2 (ja) | ピオグリタゾン塩酸塩の製造方法 | |
JP5473303B2 (ja) | 2−ブロモ−3−{4−[2−(5−エチル−2−ピリジル)エトキシ]フェニル}プロピオン酸メチルの製造方法 | |
JP5205971B2 (ja) | テトラヒドロピラン化合物の製造方法 | |
JP6868890B2 (ja) | 環上に置換基を有する含窒素環状化合物の製造方法 | |
JP2009203197A (ja) | 5−{4−[2−(5−エチル−2−ピリジル)エトキシ]ベンジル}−2−イミノ−4−チアゾリジノンの製造方法 | |
JP2005053836A (ja) | アセトアミジン誘導体の製造方法 | |
KR100771655B1 (ko) | 라베프라졸 및 그 중간체의 제조방법 | |
JP2023155765A (ja) | アミド化合物の製造方法 | |
CN106458965A (zh) | 杂芳基羧酸酯衍生物的制造方法及其制造中间体 | |
JP2009013091A (ja) | ピオグリタゾン塩酸塩の製造方法 | |
JP3959178B2 (ja) | ヒドラジン誘導体の製造方法、その中間体および中間体の製造方法 | |
CN115093399A (zh) | 一种抗痛风药物托匹司他的制备方法 | |
JP2004075616A (ja) | 4−ハロゲノ−2−(4−フルオロフェニルアミノ)−5,6−ジメチルピリミジンの製造方法 | |
JP2000264878A (ja) | 1−[(シクロペント−3−エン−1−イル)メチル]−5−エチル−6−(3,5−ジメチルベンゾイル)−2,4−ピリミジンジオンの製造方法 | |
JPS6157552A (ja) | 3−アミノピロリジンまたはその塩の製法 | |
JPH11315068A (ja) | 2,3,5,6―テトラフルオロピリジンの製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200980135056.5 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09819073 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2010532869 Country of ref document: JP |
|
ENP | Entry into the national phase |
Ref document number: 20117004006 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1901/DELNP/2011 Country of ref document: IN |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 09819073 Country of ref document: EP Kind code of ref document: A1 |