Method for producing cyclized products by cyclization reaction accompanied by dehydration condensation, and method for producing 1,3,4-substituted-pyrazole-5-carboxylic acid esters

Abstract

To provide a production method of a cyclization product in a cyclization reaction involving dehydration condensation in which no removal step of by-product water, such as an azeotropic dehydration operation or addition of an inorganic solid dehydrator requiring a filtration step after the reaction, is needed, and as an invention of the embodiment, to provide a simple and advantageous production method at an industrial scale in producing 1,3,4-substituted pyrazole-5-carboxylic acid esters useful as important intermediates in medical and agrochemical field and the like.SOLUTION: Invented is a reaction method which uses carbonic acid esters as a dehydrator in a cyclization reaction involving dehydration condensation. More concretely, invented is a production method at an industrial scale of 1,3,4-substituted pyrazole-5-carboxylic acid esters which uses carbonic acid esters as a dehydrator in a cyclization reaction of a hydrazino acetic acid ester derivative.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a novel method for producing cyclization products such as 1,3,4-substituted-pyrazole-5-carboxylic acid esters by a cyclization reaction accompanied by dehydration condensation, which does not require the removal of water produced as a by-product. Specifically, the present invention relates to an industrial method for producing 1,3,4-substituted-pyrazole-5-carboxylic acid esters, which are useful as important intermediates in the fields of medicine, agrochemicals, etc., using the production method. [Background technology]

[0002] Conventionally, 1,3,4-substituted pyrazole-5-carboxylic acid esters have been produced by chloromethylating the 4-position of 1,3-dimethylpyrazole-5-carboxylic acid ester, followed by dechlorination under reducing conditions to introduce a methyl group, as described in Patent Documents 1 and 2. However, this method has problems, such as the production of toxic bis(chloromethyl) ether during the 4-chloromethylation of 1,3-dimethylpyrazole-5-carboxylic acid ester. Patent Document 3 also describes the synthesis of ethyl 1,3,4-trimethylpyrazole-5-carboxylate by reacting an intermediate synthesized using ethyl bromoacetate, dimethyl sulfide, and diacetyl with monomethylhydrazine. However, the process requires four steps, resulting in a low yield of 10%, and requires the use of dimethyl sulfide, which has a foul odor.

[0003] On the other hand, Patent Document 4 describes a method for obtaining 1,3,4-trimethylpyrazole-5-carboxylic acid esters by subjecting a hydrazinoacetic acid ester derivative to a cyclization reaction in the presence of a base. In this reaction, the hydrazinoacetic acid ester derivative is subjected to azeotropic dehydration before the reaction. Furthermore, as a dehydration method other than azeotropic dehydration, the addition of an inorganic solid dehydrating agent such as calcium chloride or molecular sieves is also described. However, these dehydrating agents require a separation procedure, such as filtration, from the target product after the reaction is completed.

[0004] Patent Documents 5 and 6 use carbonate esters in pyrazole synthesis. However, Patent Document 5 improves the yield from 40% to 85% by using dimethyl carbonate as a solvent and molecular sieves as a dehydrating agent (comparison between Example 1 and Example 2), but does not state that carbonate esters are effective as dehydrating agents. Patent Document 6 describes a method for producing 1,3-dialkylpyrazole-4-carboxylic acid in which the use of carbonate esters prevents a decrease in yield even when the reaction temperature is increased, but does not state that the dehydrating effect of carbonate esters improves the yield. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Laid-Open No. 2001-342178 [Patent Document 2] Japanese Patent Application Laid-Open No. 2008-007503 [Patent Document 3] International Publication No. 2010 / 045764 [Patent Document 4] Japanese Patent Application Laid-Open No. 2008-208047 [Patent Document 5] Japanese Patent Application Laid-Open No. 2001-58982 [Patent Document 6] Japanese Patent Application Laid-Open No. 2000-212166 Summary of the Invention [Problem to be solved by the invention]

[0006] As described above, currently known methods for producing 1,3,4-substituted-pyrazole-5-carboxylic acid esters require a dehydration step from a liquid phase by azeotropic dehydration and a filtration step using an inorganic solid dehydrating agent, and are not necessarily industrially satisfactory in terms of the yield of the target product. Therefore, there has been a demand for a method for producing the compound using a dehydrating agent that does not require complicated post-treatment.

[0007] In view of the above circumstances, an object of the present invention is to provide a method for producing a cyclization product based on a new reaction with high yield, which does not require azeotropic dehydration or a filtration step using an inorganic solid dehydrating agent. One embodiment of this production method is to provide 1,3,4-substituted-pyrazole-5-carboxylic acid esters useful as pharmaceutical and agricultural intermediates by a cyclization reaction of a hydrazinocarboxylic acid ester derivative. [Means for solving the problem]

[0008] As a result of intensive investigations to solve the above-mentioned problems, the present inventors have found that by using a carbonate ester in a cyclization reaction accompanying dehydration condensation, such as the cyclization of a hydrazinoacetate ester derivative to obtain a 1,3,4-substituted-pyrazole-5-carboxylic acid ester, the carbonate ester functions as a dehydrating agent, thereby providing a reaction method that does not require azeotropic dehydration for removing by-product water generated in the dehydration condensation reaction to increase yield, or a step for filtering the inorganic solid dehydrating agent used.In fact, it has been found that by using a carbonate ester as if it were a solvent when obtaining a 1,3,4-substituted-pyrazole-5-carboxylic acid ester by the dehydration cyclization of a hydrazinoacetate ester derivative, the 1,3,4-substituted-pyrazole-5-carboxylic acid ester can be obtained in high yield even when by-product water is present in the reaction system.

[0009] In short, the present invention was accomplished based on the discovery that, when carbonates are used in a cyclization reaction accompanying dehydration condensation, they function as dehydrating agents, and that 1,3,4-substituted-pyrazole-5-carboxylic acid esters, which are cyclization products obtained from, for example, hydrazinoacetic acid ester derivatives, can be easily produced on an industrial scale without the need for complicated post-treatment.

[0010] That is, the present invention provides a method for producing a cyclization product by using a carbonate ester as a dehydrating agent in a cyclization reaction accompanied by dehydration condensation. More specifically, the present invention provides: General formula (1) [ka] (wherein R1 to R3 represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R4 represents an alkyl group having 1 to 4 carbon atoms), is reacted with a carbonate ester as a dehydrating agent in the presence of a base. General formula (2) [ka] (wherein R1 to R4 have the same meanings as above), [Effects of the Invention]

[0011] The use of a carbonate ester in the cyclization reaction accompanying dehydration condensation of the present invention eliminates the need for azeotropic dehydration or the use of an inorganic solid dehydrating agent and a filtration step therefor, which are used to shift the equilibrium and increase the yield, and provides an industrial method for producing a cyclized product that can produce the cyclized product in high yield.In addition, in the method of producing 1,3,4-substituted-pyrazole-5-carboxylic acid esters from hydrazinoacetic acid ester derivatives by the cyclization reaction accompanying dehydration condensation of the present invention, the use of a carbonate ester as a dehydrating agent serves as an effective dehydrating agent for water generated as a by-product in the reaction, eliminating the need for the azeotropic dehydration step or the filtration step for the inorganic solid dehydrating agent, and providing a simple and convenient method that enables the cyclized compound to be produced industrially and more advantageously. DETAILED DESCRIPTION OF THE INVENTION

[0012] The production method of the present invention will be explained in more detail below. The present invention relates to a method for producing a cyclization product, in which a carbonate ester is used as a dehydrating agent in a cyclization reaction accompanied by dehydration condensation. The cyclization reaction of the present invention involves dehydration condensation, and is, for example, a reaction as shown in the below-described reaction formula (A) in which a hydrazinoacetate derivative (1) is used as a starting material, and in the presence of a base, the hydrogen at the α-position of the acetate ester is abstracted to produce an enolate, which then attacks the carbon of the carbonyl group, resulting in intramolecular cyclization with the by-product of water. Examples of such intramolecular cyclization reactions include, for example, an intramolecular aldol reaction. Furthermore, the "cyclization product" as used herein refers to a compound obtained by a cyclization reaction accompanied by dehydration condensation, in which intramolecular cyclization has occurred to form a ring, and is usually the compound to be manufactured.

[0013] Examples of carbonate esters that can be used as dehydrating agents include dimethyl carbonate, diethyl carbonate, dimethyl dicarbonate, diethyl dicarbonate, and di-t-butyl dicarbonate. These carbonate esters can be used alone or in combination of two or more.

[0014] As for the reaction method, the carbonate ester can be used as if it were a solvent. When a solvent is used, the carbonate ester can be added together with the starting materials to the reaction system, or when no solvent is used, the carbonate ester can be added alone to the reaction system, and the starting materials can be reacted as is. This simple reaction method does not require an operation for removing by-product water generated by dehydration condensation, such as a dehydration operation by azeotropic dehydration, during the reaction, and allows the cyclization product to be produced by this simple reaction method.

[0015] In addition, a solvent and a catalyst can be used during the reaction as needed, but the reaction conditions, including the amounts of the starting materials and carbonate esters charged, as well as the reaction temperature, reaction pressure, and reaction time, are appropriately selected depending on the type of cyclization product to be obtained by the reaction. Typically, the reaction can be carried out using 1.0 to 10.0 equivalents of carbonate esters per equivalent of the starting materials, at a reaction temperature of 10 to 70°C, and for a reaction time of about 15 hours.

[0016] The reason why carbonate esters can be used to obtain cyclized products in high yields without dehydrating the by-product water is believed to be that the by-product water reacts with the carbonate esters to remove water and prevent hydrolysis of the ester, based on the interactions between the by-product water, starting materials, cyclized products, and carbonate esters in the reaction system. Similar effects have also been observed in other intramolecular cyclization reactions that involve dehydration condensation and generate by-product water, which have a similar reaction mechanism to the reaction described below in which a hydrazinoacetic acid ester derivative is intramolecularly cyclized to obtain a 1,3,4-substituted-pyrazole-5-carboxylic acid ester by dehydration condensation. Examples of methods for producing cyclized products using such intramolecular cyclization reaction using other starting materials include the following. [ka] Here, R is an alkyl group having 1 to 4 carbon atoms.

[0017] Next, a specific method for producing a 1,3,4-substituted-pyrazole-5-carboxylic acid ester according to the present invention will be described. This method produces a 1,3,4-substituted-pyrazole-5-carboxylic acid ester represented by general formula (2) by using a carbonate ester as a dehydrating agent in the cyclization reaction of a hydrazinoacetic acid ester derivative (1). This reaction process is shown in the following reaction formula (A). [ka] Reaction formula (A)

[0018] In the compounds of formulas (1) and (2), the substituents R1 to R3 represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R4 represents an alkyl group having 1 to 4 carbon atoms. Examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a normal butyl group, an isobutyl group, a s-butyl group, and a t-butyl group.

[0019] The production method of the present invention can be carried out by reacting a hydrazinoacetic acid ester derivative in the presence of a base and a carbonate ester as a dehydrating agent for a predetermined time at a predetermined temperature and under a predetermined pressure.

[0020] Carbonate esters that can be used as dehydrating agents include dimethyl carbonate, diethyl carbonate, dimethyl dicarbonate, diethyl dicarbonate, and di-t-butyl dicarbonate. These can be used alone or in combination of two or more. Among these, carbonate esters are preferred, with dimethyl carbonate and diethyl carbonate being particularly preferred. The amount of dehydrating agent used is preferably 0.5 to 10.0 equivalents, and particularly preferably 1 to 3 equivalents, relative to the substrate hydrazinoacetic acid ester derivative (1).

[0021] Examples of bases that can be used in the reaction and serve as catalysts include alkali metal carbonates such as potassium carbonate and sodium carbonate, metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium t-butoxide, and organic bases such as pyridine, morpholine, and triethylamine. These bases can be used alone or in combination of two or more. Among these, metal alkoxides are preferred, with sodium methoxide and sodium ethoxide being particularly preferred. These metal alkoxides may be used in the form of alcohol solutions or simple powders. The amount of base used is preferably 0.5 to 5 equivalents, and particularly preferably 1.0 to 1.5 equivalents, relative to the substrate hydrazinoacetic acid ester derivative (1).

[0022] The reaction temperature is preferably 10 to 70°C, and more preferably 30 to 50°C. The reaction time is preferably 1 to 5 hours, more preferably 2 to 3 hours. Within these conditions, the 1,3,4-substituted-pyrazole-5-carboxylic acid ester can be obtained in a high yield of 80% or more. Furthermore, regarding the reaction pressure, it is preferable to carry out the reaction at normal pressure from the viewpoint of operability, but in view of the vapor pressure of the reaction system and the reaction temperature, the reaction may be carried out under reduced or increased pressure.

[0023] Furthermore, a solvent can be used as needed from the viewpoint of the solubility and reactivity of the starting materials and cyclization product. The solvent to be used will vary depending on the type of starting materials and cyclization product, but generally, aliphatic hydrocarbon solvents, alicyclic hydrocarbon solvents, aromatic solvents, alcohol solvents, ester solvents, etc. are preferred. These solvents can be used alone or in combination of two or more. Specifically, methanol, ethanol, etc. are preferred from the viewpoint of dissolving the base. The amount of solvent used is preferably 50 to 100 parts by mass, more preferably about 80 parts by mass, per 100 parts by mass of the hydrazinoacetic acid ester derivative (1).

[0024] After the reaction is completed, the reaction mixture is treated by a commonly known method such as neutralization or washing and separation, and then the 1,3,4-substituted-pyrazole-5-carboxylic acid ester can be isolated by a method such as distillation. Here, when performing neutralization, washing, or separation, a solvent can be added to the reaction liquid. Examples of solvents that can be used include the above-mentioned solvents that can be used in the reaction. In consideration of the efficiency of washing or separation, a solvent that separates from water is preferred, and the amount of solvent is preferably about 150 parts by mass per 100 parts by mass of the obtained 1,3,4-substituted-pyrazole-5-carboxylic acid ester. In the treatment after the completion of the above reaction, the product yield can be improved by 3 to 5% by adding a concentration step prior to washing, in which the product is concentrated after neutralization and then washed. In order to obtain a valuable cyclized product, incorporating a concentration step is also a preferred production method.

[0025] The hydrazinoacetic acid ester derivative of general formula (1) can be synthesized in accordance with the method described in JP-A-2008-208047 by reacting a hydrazine with a halogenoacetic acid ester such as a bromoacetic acid ester, a chloroacetic acid ester, or an iodoacetic acid ester, followed by reaction with diacetyl. [Example]

[0026] The present invention and its embodiments will be described in detail below with reference to examples, but the scope of the present invention is not limited to these examples. In the following examples and comparative examples, high performance liquid chromatography (HPLC) was used to calculate yields.

[0027] Reference example 1 Synthesis of methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate A 2L four-neck flask was charged with 149.7g (3.25mol) of monomethylhydrazine, 520.7g (16.25mol) of methanol, and 296.0g (2.93mol) of triethylamine and cooled to 5°C with stirring. 497.2g (3.25mol) of methyl bromoacetate was added dropwise over 2 hours. The reaction was continued for 1 hour, followed by the dropwise addition of 265.8g (3.09mol) of diacetyl over 1.5 hours, and the reaction was continued for 19 hours at 10°C. The resulting reaction solution was concentrated under reduced pressure, and 900.0g of toluene and 404.8g of water were added and stirred. The aqueous layer was removed by separation, and 147.2g of water was added to the toluene layer for washing. After removing the aqueous layer by separation, the toluene layer was concentrated under reduced pressure to obtain 541.2g of methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate. The yield was 74.7% based on the amount of methyl bromoacetate used.

[0028] Reference example 2 Synthesis of ethyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate A 3L four-neck flask was charged with 149.7g (3.25mol) of monomethylhydrazine, 748.6g (16.25mol) of ethanol, and 296.0g (2.93mol) of triethylamine and cooled to 5°C with stirring. 542.8g (3.25mol) of ethyl bromoacetate was added dropwise over 2 hours. The reaction was continued for 1 hour, followed by the dropwise addition of 265.8g (3.09mol) of diacetyl over 1.5 hours, and the reaction was continued for 19 hours at 10°C. The resulting reaction solution was concentrated under reduced pressure, and 900.0g of toluene and 404.8g of water were added and stirred. The aqueous layer was removed by separation, and 147.2g of water was added to the toluene layer for washing. After removing the aqueous layer by separation, the toluene layer was concentrated under reduced pressure to obtain 551.2g of ethyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate. The yield was 72.0% based on the amount of ethyl bromoacetate used.

[0029] Example 1 Synthesis of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester using dimethyl carbonate as a dehydrating agent A 2L four-neck flask was charged with 247.7g (1.28mol) of 28% sodium methoxide methanol solution and 192.8g (2.15mol) of dimethyl carbonate, and the mixture was heated to 40°C with stirring. 229.4g (1.07mol) of methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate was added dropwise over 2.0 hours. The reaction was continued at 40°C for 2 hours. After the reaction, the mixture was cooled to 20°C and neutralized with 129.3g (1.24mol) of hydrochloric acid. The neutralized solution was concentrated under reduced pressure of 10kPa, and 345.1g of toluene and 264.8g of water were added and stirred. The aqueous layer was removed, and the toluene layer was washed with water. After removing the wash water, the toluene layer contained 29.9wt% of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester. The yield based on the methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate used up to this point was 88.2%. The yield of hydrolyzed 1,3,4-trimethylpyrazole-5-carboxylic acid was 5.3%. Furthermore, when the product was washed without concentration after neutralization with hydrochloric acid, the yield was 84.9%, demonstrating that the addition of the concentration step improved the yield.

[0030] Example 2 Synthesis of 1,3,4-trimethylpyrazole-5-carboxylic acid ethyl ester using diethyl carbonate as a dehydrating agent A 3L four-neck flask was charged with 816.6g (2.40mol) of 20% sodium ethoxide ethanol solution and 472.5g (4.00mol) of diethyl carbonate, and the temperature was raised to 40°C with stirring. 479.3g (2.00mol) of ethyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate was added dropwise over 2.5 hours. The reaction was continued at 40°C for 2 hours. After the reaction, the mixture was cooled to 20°C and neutralized with 233.7g (2.24mol) of hydrochloric acid. 654.0g of toluene and 504.3g of water were added and stirred. The aqueous layer was removed, and the toluene layer was washed with water. After removing the wash water, the toluene layer contained 17.4wt% of 1,3,4-trimethylpyrazole-5-carboxylic acid ethyl ester. The yield based on the ethyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate used up to this point was 85.3%, and the yield of hydrolyzed 1,3,4-trimethylpyrazole-5-carboxylic acid was 6.9%.

[0031] Comparative Example 1 Synthesis of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester without using a dehydrating agent A 2L four-neck flask was charged with 247.7g (1.28mol) of 28% sodium methoxide methanol solution and heated to 40°C with stirring. 229.4g (1.07mol) of methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate was added dropwise over 2.0 hours. The reaction was continued at 40°C for 2 hours. After the reaction, the mixture was cooled to 20°C and neutralized with 129.3g (1.24mol) of hydrochloric acid. 345.1g of toluene and 264.8g of water were added and stirred. The aqueous layer was removed, and the toluene layer was washed with water. After removing the wash water, the toluene layer contained 11.5wt% of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester. The yield based on the methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate used up to this point was 25.8%, and the yield of hydrolyzed 1,3,4-trimethylpyrazole-5-carboxylic acid was 42.8%.

[0032] Comparative Example 2 Synthesis of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester by dehydration before reaction A 500 ml four-neck flask was charged with 32.2 g (0.15 mol) of methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate, 10.0 g (0.11 mol) of toluene, and 300.0 g (9.36 mol) of methanol and heated under atmospheric pressure. A 31.3 g fraction was collected and the water content in the system was removed. After ice cooling, 20.7 g (0.15 mol) of potassium carbonate was added and the mixture was heated under reflux for 4 hours. After ice cooling, the methanol was recovered under reduced pressure, and 100 g of water and 100 g of normal hexane were added to extract the organic matter. The aqueous layer was further extracted with 30 g of normal hexane, and the organic layers were mixed. The organic layer contained 1.4 wt% of 1,3,4-trimethylpyrazole-5-carboxylic acid methyl ester. The yield based on the methyl 2-[(1-aza-2-methyl-3-oxobut-1-enyl)methylamino]acetate used up to this point was 7.1%, and the yield of hydrolyzed 1,3,4-trimethylpyrazole-5-carboxylic acid was 70.1%. [Industrial Applicability]

[0033] According to the present invention, in the production of 1,3,4-substituted-pyrazole-5-carboxylic acid esters used as pharmaceutical and agrochemical intermediates, removing the water by-produced during the reaction is important for completing the reaction and obtaining the target product in high yield. The use of carbonate esters as dehydrating agents enables a simple dehydration procedure, allowing the target product to be obtained in high yield. Furthermore, when an inorganic solid dehydrating agent is used to remove the water by-produced during the reaction, a step of separating the dehydrating agent by filtration or the like is required after the reaction is completed, which requires a great deal of labor and time for mass production. On the other hand, the method of the present invention does not require the problematic complicated operations, making it possible to provide a simple and economical industrial production method, and the present invention is of great significance in the pharmaceutical and agrochemical fields.

Claims

【Request Item 1】 General form (1) 【Chemistry 1】 (In the formula, R １ From R ３ represents a methyl group, R ４ represents an alkyl group having 1 to 4 carbon atoms, the reaction temperature is set to 10 to 40° C., and in the presence of a base in an amount of 0.5 to 5 equivalents relative to the hydrazinoacetic acid ester derivative, one or more carbonate esters selected from the group consisting of dimethyl carbonate, diethyl carbonate, dimethyl dicarbonate, and diethyl dicarbonate are used as a dehydrating agent. General form (2) 【Chemistry 2】 (In the formula, R １ From R ４ has the same meaning as above.)

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