Method for producing benzyl hydrazine derivative

Abstract

To provide a method for producing a benzyl hydrazine derivative with high purity.SOLUTION: In one aspect, a method for producing a benzyl hydrazine derivative is provided. The production method includes: contacting a benzyl derivative represented by formula (I) with a hydrazine compound to produce a benzyl hydrazine derivative represented by formula (II); and contacting a first mixture with a first separation liquid to separate them into a first organic layer and a first aqueous layer. The first mixture contains a benzyl hydrazine derivative represented by formula (II), a hydrazine compound, and a first organic solvent. The first separation liquid contains water.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a benzylhydrazine derivative. [Background technology]

[0002] Methyl N-(4,6-diamino-2-{1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}pyrimidin-5-yl)-N-methylcarbamate, also known as riociguat (ROC), is a type of guanylate cyclase activator and stimulator. Riociguat has the following formula:

[0003] [ka]

[0004] By reacting (2-fluorobenzyl)hydrazine represented by the following formula (IIa) with a compound represented by the following formula (III), ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate represented by the following formula (IVa) can be obtained. These compounds can be used as intermediates for synthesizing riociguat.

[0005] [ka]

[0006] [ka]

[0007] [ka] [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2017 / 025981 [Patent Document 2] China Patent Application Publication No. 105237531 [Non-patent literature]

[0009] [Non-Patent Document 1] J. Med. Chem., 1995, 38, 3884-3888 Summary of the Invention [Problem to be solved by the invention]

[0010] An object of the present invention is to provide a method for producing a benzylhydrazine derivative containing fewer impurities. [Means for solving the problem]

[0011] According to one aspect, a method for producing a benzylhydrazine derivative is provided. The method includes contacting a benzyl derivative represented by the following formula (I) with a hydrazine compound to obtain a benzylhydrazine derivative represented by the following formula (II), and contacting a first mixture with a first separated liquid to separate into a first organic layer and a first aqueous layer. The first mixture contains the benzylhydrazine derivative represented by the formula (II), the hydrazine compound, and a first organic solvent. The first separated liquid contains water.

[0012] [ka]

[0013] In formula (I), X is a halogen atom or an alkyl group having 1 to 3 carbon atoms, Y is a halogen atom, a mesyl group, or a tosyl group, and a is an integer of 0 to 3.

[0014] [ka]

[0015] In formula (II), X and a have the same meanings as those in formula (I).

[0016] According to another embodiment, there is provided a method for producing a pyrazole derivative, which comprises contacting the first organic layer obtained by the method according to the embodiment with a compound represented by the following formula (III) to obtain a pyrazole derivative represented by the following formula (IV):

[0017] [ka]

[0018] [ka]

[0019] In formula (IV), X and a have the same meanings as in formula (I). Effect of the Invention

[0020] According to the present invention, there is provided a method for producing a benzylhydrazine derivative with few impurities. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] According to an embodiment, a method for producing a benzylhydrazine derivative is provided. The benzylhydrazine derivative can be used as an intermediate for synthesizing a drug substance such as riociguat. The method includes contacting a benzyl derivative represented by formula (I) with a hydrazine compound to obtain a benzylhydrazine derivative represented by formula (II), and contacting a first mixture with a first separation liquid to separate into a first organic layer and a first aqueous layer. The first mixture includes the benzylhydrazine derivative represented by formula (II), the hydrazine compound, and a first organic solvent. The first separation liquid includes water.

[0022] According to this production method, it is possible to produce a benzylhydrazine derivative with few impurities. The reason for this is believed to be as follows.

[0023] First, as described in Patent Document 1, ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate represented by the above formula (IVa) can be obtained by the following method. First, 2-fluorobenzyl chloride is added to an aqueous solution of hydrazine monohydrate, and then dimethylchloroethane is added to the resulting reaction solution to separate the liquids. A solution of hydrochloric acid and ethyl acetate is added to the resulting organic layer to precipitate a solid. The resulting solid is dissolved in isopropanol, and then cooled to reprecipitate the solid. In this way, crystals of (2-fluorobenzyl)hydrazine hydrochloride represented by the above formula (IIa) are obtained. The obtained crystals of (2-fluorobenzyl)hydrazine hydrochloride are reacted with a compound represented by the above formula (III), which is a reaction product of diethyl oxalate, methyl tertiary butyl ether, and sodium methoxide, to obtain ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate represented by the above formula (IVa).

[0024] The reason why the crystals of (2-fluorobenzyl)hydrazine hydrochloride are reacted with the compound represented by formula (III) after the crystals are obtained is believed to be to remove the hydrazine monohydrate remaining unreacted in the reaction between hydrazine monohydrate and 2-fluorobenzyl chloride. That is, the present inventors have found that hydrazine monohydrate can inhibit the reaction between (2-fluorobenzyl)hydrazine and the compound represented by formula (III). Therefore, when a mixture of (2-fluorobenzyl)hydrazine and hydrazine monohydrate is reacted with the compound represented by formula (III), it is difficult to obtain ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate in a sufficient yield. Therefore, it is believed that it is necessary to remove hydrazine monohydrate from the crystals of (2-fluorobenzyl)hydrazine hydrochloride by crystallization treatment.

[0025] In the method according to the embodiment, the first mixture containing the benzylhydrazine derivative represented by formula (II) and the hydrazine compound is subjected to a separation treatment using a first separation liquid. This allows separation into an organic layer containing the benzylhydrazine derivative and an aqueous layer containing the hydrazine compound. The organic layer thus obtained selectively contains the benzylhydrazine derivative and has a low content of the hydrazine compound. Therefore, this organic layer can be subjected to a reaction with the compound represented by formula (III) above, and a pyrazole derivative represented by formula (IV) below can be obtained with a high yield. That is, according to the method according to the embodiment, the crystallization treatment can be omitted, and the benzylhydrazine derivative and the hydrazine compound can be separated by a separation treatment, so that the benzylhydrazine derivative with few impurities can be efficiently obtained. Furthermore, this benzylhydrazine derivative is an unstable compound that is easily decomposed. According to the method according to the embodiment, the organic layer obtained by this separation treatment can be used for a reaction with the compound represented by formula (III), so that there is no need to store the solid of the benzylhydrazine derivative for a long period of time, and the next reaction can be carried out continuously. Therefore, according to this production method, the pyrazole derivative can be efficiently produced with a small number of steps.

[0026] [ka]

[0027] In formula (IV), X and a have the same meanings as in formula (I).

[0028] The manufacturing method according to the embodiment will be described in detail below.

[0029] (Production of benzylhydrazine derivatives) This production method includes contacting a benzyl derivative represented by formula (I) with a hydrazine compound to obtain a benzylhydrazine derivative represented by formula (II), and contacting a first mixture with a first separation liquid to separate into a first organic layer and a first aqueous layer.

[0030] The first mixture contains a benzylhydrazine derivative represented by formula (II), a hydrazine compound, and a first organic solvent. The first mixture is obtained, for example, by contacting a benzyl derivative represented by formula (I) with a hydrazine compound in the presence of a first organic solvent.

[0031] The benzyl derivative represented by formula (I) can be synthesized by a known method.

[0032] [ka]

[0033] In formula (I), X is a halogen atom or an alkyl group having a carbon number of 1 to 3. X is preferably a halogen atom, more preferably iodine, fluorine or bromine, and further preferably fluorine.

[0034] Y is a halogen atom, a mesyl group, or a tosyl group. Y is preferably a halogen atom, more preferably iodine, fluorine, or bromine, and further preferably bromine.

[0035] a is an integer of 0 to 3. a is preferably 1.

[0036] The benzyl derivative is preferably 2-fluorobenzyl bromide represented by the following formula (Ia): This compound is more suitable as a raw material of an intermediate for the synthesis of riociguat.

[0037] [ka]

[0038] As the hydrazine compound, hydrazine (NH2-NH2) or a hydrazine derivative is used. As the hydrazine compound, for example, at least one compound selected from the group consisting of hydrazine monohydrate (N2H4·H2O), hydrazine monohydrochloride, and hydrazine dihydrochloride is used. As the hydrazine compound, it is preferable to use hydrazine monohydrate.

[0039] The amount of the hydrazine compound relative to 1 mole of the benzyl derivative represented by formula (I) is, for example, 5 moles or more, that is, 5 molar equivalents or more. When the amount of the hydrazine compound is large, the amount of impurities tends to decrease. The amount of the hydrazine compound relative to 1 mole of the benzyl derivative represented by formula (I) is preferably 7 moles or more. On the other hand, the hydrazine compound may be toxic and flammable. From the viewpoint of danger, the amount of the hydrazine compound is preferably 15 moles or less, more preferably 12 moles or less.

[0040] The contact between the benzyl derivative represented by formula (I) and the hydrazine compound is carried out, for example, in the air at a temperature in the range of -10°C to 80°C. The reaction temperature is preferably in the range of -10°C to 40°C, more preferably in the range of -5°C to 20°C. If the reaction temperature is high, the yield of the benzylhydrazine derivative represented by formula (II) tends to increase. On the other hand, if the reaction temperature is excessively high, impurities tend to be generated.

[0041] The contact between the benzyl derivative represented by formula (I) and the hydrazine compound is carried out for, for example, 0.5 to 12 hours, and the reaction time is preferably 1 to 6 hours.

[0042] The benzyl derivative represented by formula (I) is contacted with the hydrazine compound in a first organic solvent. The first organic solvent is preferably a solvent capable of dissolving the hydrazine compound and immiscible with water. As the first organic solvent, for example, at least one compound selected from the group consisting of ethanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, tetrahydrofuran, and 2-methyltetrahydrofuran is used. The first organic solvent preferably contains at least one compound selected from the group consisting of 1-butanol and 2-butanol, and more preferably contains 2-butanol. The use of these solvents allows the hydrazine compound to be efficiently removed.

[0043] The amount of the first organic solvent relative to 1 g of the benzyl derivative represented by formula (I) is, for example, 1 mL or more and 50 mL or less. The amount of the first organic solvent is preferably 3 mL or more and 16 mL or less, and more preferably 5 mL or more and 12 mL or less.

[0044] The contact between the benzyl derivative represented by formula (I) and the hydrazine compound is preferably carried out by dropping the benzyl derivative represented by formula (I) into a hydrazine solution obtained by dissolving the hydrazine compound in the first organic solvent. The contact between the benzyl derivative represented by formula (I) and the hydrazine compound may also be carried out by dropping the hydrazine compound into a benzyl derivative solution obtained by dissolving the benzyl derivative represented by formula (I) in the first organic solvent.

[0045] The benzyl derivative represented by formula (I) may be contacted with the hydrazine compound in a mixed solvent of a first organic solvent and water. The volume ratio V1 / V3 of the volume V1 of the first organic solvent to the volume V3 of the water is, for example, 0.1 to 5, and for another example, 0.5 to 2.

[0046] The reaction of the benzyl derivative represented by formula (I) with the hydrazine compound produces a first mixture containing a benzylhydrazine derivative represented by formula (II) below and a first organic solvent. The first mixture further contains, as a type of impurity, the hydrazine compound that remains unreacted in the reaction of the benzyl derivative represented by formula (I) with the hydrazine compound.

[0047] [ka]

[0048] In formula (II), X and a have the same meanings as in formula (I).

[0049] When a benzyl derivative in which X is fluorine, such as the above-mentioned 2-fluorobenzyl bromide, is used, the (2-fluorobenzyl)hydrazine represented by the above-mentioned formula (IIa) is obtained. The (2-fluorobenzyl)hydrazine is useful as an intermediate for synthesizing riociguat.

[0050] The first mixture may further contain impurities other than the hydrazine compound, such as a first dimer represented by the following formula (III), a second dimer represented by the following formula (IV), the benzyl derivative represented by the following formula (I), and other compounds.

[0051] [ka]

[0052] In formula (III), X and a have the same meanings as in formula (I).

[0053] [ka]

[0054] In formula (IV), X and a have the same meanings as in formula (I).

[0055] When a benzyl derivative in which X is fluorine, such as 2-fluorobenzyl bromide represented by formula (Ia), is used as a raw material, it is considered that a first dimer represented by the following formula (IIIa) and a second dimer represented by the following formula (IVa) are obtained.

[0056] [ka]

[0057] [ka]

[0058] The first mixture may be obtained by contacting the benzyl derivative represented by formula (I) with a hydrazine compound in the presence of a third organic solvent to obtain a second mixture, and then mixing the second mixture with the first organic solvent. The second mixture contains the same compounds as the first mixture, except that it contains the third organic solvent and does not contain the first organic solvent.

[0059] The third organic solvent may be the first water-soluble organic solvent, or may be the same type of organic solvent as the first organic solvent described above.

[0060] The first water-soluble organic solvent is a compound having a structure different from that of the first organic solvent. The first water-soluble organic solvent is preferably a solvent capable of dissolving the hydrazine compound and being uniformly miscible with the first separated liquid. As the first water-soluble organic solvent, for example, at least one compound selected from the group consisting of 1-propanol, 2-propanol, and t-butanol is used.

[0061] The amount of the first water-soluble organic solvent relative to 1 g of the benzyl derivative represented by formula (I) is, for example, 1 mL or more and 20 mL or less, preferably 2 mL or more and 15 mL or less, more preferably 3 mL or more and 10 mL or less.

[0062] The amount of the first organic solvent added to the second mixture is, for example, 2 mL to 40 mL, preferably 4 mL to 30 mL, more preferably 6 mL to 20 mL.

[0063] The ratio V1 / V2 of the volume V1 of the first organic solvent to the volume V2 of the first water-soluble organic solvent is, for example, 1 or more and 10 or less, and preferably 1.5 or more and 4 or less.

[0064] The contact conditions of the benzyl derivative represented by formula (I) and the hydrazine compound are the same as those in the contact in the presence of the first organic solvent described above. The contact of the benzyl derivative represented by formula (I) and the hydrazine compound is preferably carried out by dropping the benzyl derivative represented by formula (I) into a hydrazine solution obtained by dissolving the hydrazine compound in the first water-soluble organic solvent. It may also be carried out by dropping the hydrazine compound into a benzyl derivative solution obtained by dissolving the benzyl derivative represented by formula (I) in the first water-soluble organic solvent.

[0065] When the first organic solvent is used as the third organic solvent, the first organic solvent may be further added to the first mixture before the first separation liquid is added. That is, the first organic solvent may be added in stages in portions. For example, the hydrazine compound may be dissolved in half of the first organic solvent to obtain a hydrazine solution, and then the benzyl derivative represented by formula (I) may be added to the hydrazine solution, the remaining first organic solvent may be added to the obtained first mixture, and then the first separation liquid may be added. In this case, the first organic solvent that dissolves the hydrazine compound and the first organic solvent added to the first mixture, i.e., the second organic solvent, may be different or the same type.

[0066] By adding the first separation liquid to the first mixture obtained by the above method, the first mixture can be separated into a first organic layer and a first aqueous layer. The first aqueous layer selectively contains a water-soluble hydrazine compound. The first organic layer contains a benzylhydrazine derivative represented by formula (II). The first organic layer is also considered to contain impurities such as a first dimer and a second dimer.

[0067] The first separation liquid contains water and is a solvent capable of separating the first mixture. The first separation liquid is preferably a solvent immiscible with the first organic solvent. The first separation liquid may contain only water, or may be saline. As the water, it is preferable to use at least one selected from the group consisting of pure water, ultrapure water, and ion-exchanged water. The concentration of the saline is preferably 10% by mass or more and 26% by mass or less, and more preferably 15% by mass or more and 25% by mass or less.

[0068] The amount of the first separation liquid per 1 g of the benzyl derivative represented by formula (I) is, for example, 1 mL or more and 10 mL or less. The amount of the first separation liquid is preferably 1 mL or more and 8 mL or less, and more preferably 2 mL or more and 6 mL or less.

[0069] The contact of the first mixture with the first separated liquid is carried out in the air at a temperature in the range of, for example, 0° C. or more and 50° C. or less. The reaction temperature is preferably in the range of 10° C. or more and 30° C. or less.

[0070] This separation treatment may be carried out multiple times, i.e., after discarding the first aqueous layer, the first separating liquid may be further added to the first organic layer to separate the first organic layer and the first aqueous layer, and the first aqueous layer may be discarded, or this operation may be further repeated.

[0071] The first organic layer obtained by the above method may be subjected to a washing treatment. The washing treatment is carried out with water or a saline solution. The washing treatment may be carried out several times.

[0072] (Method of producing pyrazole derivative) The first organic layer containing the benzylhydrazine derivative represented by formula (II) obtained by the above method is contacted with a compound represented by formula (III) below to obtain a third mixture containing a pyrazole derivative represented by formula (IV) below.

[0073] [ka]

[0074] [ka]

[0075] In formula (IV), X and a have the same meanings as in formula (I).

[0076] The amount of the compound represented by formula (III) relative to 1 mole of the benzylhydrazine derivative represented by formula (II) is, for example, 0.4 moles or more and 2 moles or less. The amount of the compound represented by formula (III) is preferably 0.6 moles or more and 1.8 moles or less, more preferably 0.8 moles or more and 1.6 moles or less.

[0077] The reaction between the first organic layer and the compound represented by the following formula (III) is preferably carried out under an inert gas atmosphere. As the inert gas, argon, nitrogen, or a mixture thereof is preferably used. The reaction temperature is preferably in the range of 20°C to 120°C, more preferably in the range of 40°C to 100°C. The contact is carried out, for example, for 0.5 hours to 12 hours. The reaction time is preferably 1 hour to 8 hours. The contact is preferably carried out under heating under reflux.

[0078] The reaction between the first organic layer and the compound represented by formula (III) is preferably carried out in the presence of a second organic solvent. As the second organic solvent, for example, at least one selected from the group consisting of 2-butanol, 1-butanol, toluene, xylene, tetrahydrofuran, and 2-methyltetrahydrofuran is used. As the second organic solvent, at least one selected from the group consisting of 2-butanol, 1-butanol, toluene, xylene, tetrahydrofuran, and 2-methyltetrahydrofuran is preferably used. The amount of the second organic solvent relative to 1 g of the compound represented by formula (III) is, for example, 1 mL or more and 20 mL or less. The amount of the second organic solvent is preferably 1 mL or more and 15 mL or less, more preferably 2 mL or more and 10 mL or less.

[0079] This contact may be carried out in the presence of an acid catalyst. For example, at least one selected from the group consisting of trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, phosphoric acid, acetic acid, formic acid, and sulfuric acid is used as the acid catalyst. It is preferable to use TFA as the acid catalyst. The amount of the acid catalyst relative to 1 mole of the compound represented by formula (I) is, for example, 0.5 moles or more and 3 moles or less. It is preferable that the amount of the acid catalyst is 1 mole or more and 1.8 moles or less.

[0080] The contact of the organic layer with the compound represented by formula (III) is preferably carried out by mixing the organic layer with a mixed liquid obtained by mixing a second organic solvent, an acid catalyst, and the compound represented by formula (III) under an inert atmosphere.

[0081] The reaction between the first organic layer containing the benzylhydrazine derivative represented by formula (II) and the compound represented by the following formula (III) may be quenched, for example, by adding saline or the like and lowering the reaction temperature.

[0082] The third mixture containing the pyrazole derivative represented by formula (IV) obtained by the above method may be subjected to a separation treatment or a washing treatment using ethyl acetate or the like. EXAMPLES

[0083] The present invention will be described in detail below with reference to examples, but the present invention is not limited by these examples. It is not limited to:

[0084] <Example 1> (Production of (2-fluorobenzyl)hydrazine) 3.2 g of hydrazine monohydrate was mixed with 4 mL of 1-butanol to obtain a hydrazine solution. 1.0 g of 2-fluorobenzyl bromide (RC-A01) was added dropwise to the hydrazine solution while stirring. The solution after the addition was stirred at 0° C. for 2 hours to obtain a first mixture. 3 mL of 20% by mass saline was added to the obtained first mixture to separate it into a first organic layer and a first aqueous layer, and the first aqueous layer was discarded. This separation process was performed two more times. In this way, a first organic layer containing (2-fluorobenzyl)hydrazine was obtained.

[0085] (Preparation of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate) The first organic layer was mixed with 0.7 g of the compound represented by formula (III) and 1.7 g of trifluoroacetic acid and stirred at room temperature, then stirred at 80°C for 2 hours. 3 mL of 10% aqueous sodium carbonate solution was added to the resulting reaction solution to separate it into an organic layer and an aqueous layer, and the aqueous layer was extracted with 3 mL of toluene. The organic layer extracted with toluene and the previous organic layer were combined to obtain a mixed organic layer, which was washed twice with 3 mL of water, and then the mixed organic layer was concentrated. 2 mL of ethyl acetate was added to the concentrated residue and dissolved by heating, and 4 mL of t-butyl methyl ether was added and stirred at 10°C or less for 4 hours. The precipitated solid was filtered and dried to obtain 4.2 g of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate.

[0086] <Example 2> (Production of (2-fluorobenzyl)hydrazine) A first mixture was obtained in the same manner as in Example 1, except that 2-butanol was used instead of 1-butanol. 3 mL of 20% by mass saline was added to the first mixture to separate it into an organic layer and an aqueous layer, and then the aqueous layer was extracted with 4 mL of 1-butanol. Sodium sulfate was added to the mixed organic layer obtained by combining the organic layer extracted with 1-butanol and the previous organic layer, and the mixture was stirred and filtered to remove solids, thereby obtaining a first organic layer containing (2-fluorobenzyl)hydrazine.

[0087] (Preparation of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate) The first organic layer was mixed with 4 mL of toluene, 0.7 g of the compound represented by formula (III), and 1.7 g of trifluoroacetic acid, and stirred at room temperature, then at 80° C. for 2 hours. 3 mL of 10% aqueous sodium carbonate solution was added to the reaction solution to separate it into an organic layer and an aqueous layer, and the aqueous layer was extracted with 3 mL of toluene. The organic layer extracted with toluene and the previous organic layer were combined to obtain a mixed organic layer, which was washed twice with 3 mL of water, and then the mixed organic layer was concentrated. 2 mL of ethyl acetate was added to the concentrated residue and dissolved by heating, and 4 mL of t-butyl methyl ether was added and stirred at 10° C. or less for 4 hours. The precipitated solid was filtered and dried to obtain 7.1 g of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate.

[0088] <Example 3> Ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate was obtained in the same manner as in Example 1, except that 12 mL of ethanol was used instead of 4 mL of 1-butanol.

[0089] <Example 4> Ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate was obtained in the same manner as in Example 1, except that 8 mL of ethanol was used instead of 4 mL of 1-butanol.

[0090] <Example 5> Ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate was obtained in the same manner as in Example 1, except that the amount of 1-butanol was changed to 8 mL.

[0091] <Example 6> Ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate was obtained in the same manner as in Example 1, except that 8 mL of 2-butanol was used instead of 4 mL of 1-butanol.

[0092] <Example 7> Ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate was obtained in the same manner as in Example 1, except that a mixed solvent of 4 mL of tetrahydrofuran and 4 mL of water was used instead of 4 mL of 1-butanol.

[0093] <Example 8> Ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate was obtained in the same manner as in Example 1, except that a mixed solvent of 4 mL of ethanol and 4 mL of water was used instead of 4 mL of 1-butanol.

[0094] <Example 9> Ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate was obtained in the same manner as in Example 2, except that the solution after the dropwise addition of RC-A01 was stirred at 0° C. for 2 hours and then further mixed with 4 mL of 2-butanol to obtain a first mixture.

[0095] <Example 10> Ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate was obtained in the same manner as in Example 1, except that 4 mL of ethanol was used instead of 4 mL of 1-butanol, and the solution after the dropwise addition of RC-A01 was stirred at 0° C. for 2 hours, and then 4 mL of 2-butanol was further mixed to obtain a first mixture.

[0096] <Example 11> Ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate was obtained in the same manner as in Example 1, except that 4.8 g of hydrazine monohydrate was used instead of 3.2 g of hydrazine monohydrate, and a mixed solvent of 4 mL of 1-butanol and 4 mL of water was used instead of 1-butanol.

[0097] <Comparative Example 1> Preparation of (2-fluorobenzyl)hydrazine 301.5 g of hydrazine monohydrate was mixed with 500 mL of water to obtain a hydrazine solution. 100 g of 2-fluorobenzyl bromide (RC-A01) was added dropwise to this hydrazine solution while stirring. The solution after the addition was stirred at a temperature of 25 to 30°C for 4 hours to obtain a first mixture. Dichloromethane was added to the obtained first mixture to separate it into a first organic layer and a first aqueous layer, and the first aqueous layer was discarded. 260 mL of hydrochloric acid / ethyl acetate solution was added to the first organic layer, and the precipitated crystals were collected by filtration. The precipitated crystals were recrystallized from 2-propanol to obtain 56.2 g of (2-fluorobenzyl)hydrazine hydrochloride. (Preparation of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate) 50g of diethyl oxalate was mixed with 250mL of t-butyl methyl ether to obtain a diethyl oxalate mixed solution. Under a nitrogen atmosphere, 28g of sodium methoxide was added to the obtained diethyl oxalate mixed solution, and the mixture was stirred at 50-55°C for 3 hours. The solvent was completely removed under reduced pressure, and 250mL of tetrahydrofuran, 39.0g of trifluoroacetic acid, and 60.4g of (2-fluorobenzyl)hydrazine hydrochloride were added, and the mixture was stirred at 70-75°C for 4 hours. After cooling to 25-30°C, water and ethyl acetate were added, and an aqueous sodium carbonate solution was further added and filtered through Celite. The obtained organic layer and aqueous layer were separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and saline, and completely removed under reduced pressure. The concentrated residue was recrystallized from t-butyl methyl ether, and the precipitated solid was collected by filtration and dried to obtain 32.0g of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate. The yield was 35.5%.

[0098] <Evaluation test> (Purity measurement of hydrazine compounds, A02 and A03) The purity of the hydrazine compounds obtained in the examples, (2-fluorobenzyl)hydrazine (A02) and 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate (A03), was measured under the following conditions. The results are shown in Table 2. Apparatus: High performance liquid chromatography (HPLC). Model: 2695-2489-2998 (Waters). Detector: ultraviolet spectrophotometer (measurement wavelength: 210 nm). Column: COSMOSIL C18, inner diameter 4.6 mm, length 25 cm (particle diameter 5 μm) (Nacalai Tesque). Column temperature: constant at 40°C. Sample temperature: constant 15°C. Mobile phase A: 0.4% perchloric acid aqueous solution Mobile phase B: Acetonitrile Mobile phase delivery: The concentration gradient is controlled by changing the mixing ratio of mobile phases A and B as shown in Table 1.

[0099] [Table 1]

[0100] Flow rate: 1.0mL / min. Measurement time: 52 minutes.

[0101] Under the above conditions, the peak positions determined by liquid chromatography were as follows: RC-A03:17.1 minutes RC-A02:3.6 minutes RC-A01:39.9 minutes Hydrazine compounds: 3.2 min

[0102] [Table 2]

[0103] Preferred aspects of the invention are set forth below. [1] contacting a benzyl derivative represented by the following formula (I) with a hydrazine compound to obtain a benzylhydrazine derivative represented by the following formula (II); contacting a first mixture containing the benzylhydrazine derivative represented by formula (II), the hydrazine compound, and a first organic solvent with a first separation liquid containing water, thereby separating the mixture into a first organic layer and a first aqueous layer; A method for producing a benzylhydrazine derivative, comprising:

[0104] [ka]

[0105] In the formula (I), X is a halogen atom or an alkyl group having 1 to 3 carbon atoms, Y is a halogen atom, a mesyl group, or a tosyl group; a is an integer between 0 and 3,

[0106] [ka]

[0107] In the above formula (II), X and a have the same meanings as in formula (I). [2] The method according to [1], wherein the first organic solvent contains at least one compound selected from the group consisting of ethanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, tetrahydrofuran, and 2-methyltetrahydrofuran. [3] The method according to [1] or [2], wherein the amount of the first organic solvent per 1 g of the benzylhydrazine derivative represented by the formula (II) is 3 mL or more and 16 mL or less. [4] The manufacturing method according to any one of [1] to [3], wherein the first separation liquid is a saline solution or water. [5] The method according to any one of [1] to [4], wherein the hydrazine compound includes hydrazine monohydrate. [6] The method according to any one of [1] to [5], wherein the amount of the hydrazine compound per mole of the benzyl derivative represented by formula (I) is 5 moles or more. [7] The method according to any one of [1] to [6], comprising contacting the benzyl derivative represented by formula (I) with the hydrazine compound in the presence of the first organic solvent to obtain the first mixture. [8] The method according to any one of [1] to [6], comprising contacting the benzyl derivative represented by formula (I) with the hydrazine compound in the presence of a second organic solvent to obtain a second mixture, and mixing the second mixture with the first organic solvent to obtain the first mixture. [9] The method according to [8], wherein the second organic solvent contains at least one compound selected from the group consisting of ethanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1-propanol, 2-propanol, and t-butanol.

[10] A method for producing a pyrazole derivative, comprising contacting the first organic layer obtained by the method according to any one of [1] to [9] with a compound represented by the following formula (III) to obtain a pyrazole derivative represented by the following formula (IV):

[0108] [ka]

[0109] [ka]

[0110] In the formula (IV), X and a have the same meanings as in formula (I).

Claims

1. contacting a benzyl derivative represented by the following formula (I) with a hydrazine compound to obtain a benzylhydrazine derivative represented by the following formula (II); contacting a first mixture containing the benzylhydrazine derivative represented by formula (II), the hydrazine compound, and a first organic solvent with a first separation liquid containing water, thereby separating the mixture into a first organic layer and a first aqueous layer; A method for producing a benzylhydrazine derivative, comprising: [Formula 1] In the formula (I), X is a halogen atom or an alkyl group having 1 to 3 carbon atoms; Y is a halogen atom, a mesyl group, or a tosyl group; a is an integer of 0 to 3, [chemical 2] In the above formula (II), X and a have the same meanings as in formula (I).

2. The method according to claim 1, wherein the first organic solvent comprises at least one compound selected from the group consisting of ethanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, tetrahydrofuran, and 2-methyltetrahydrofuran.

3. The method according to claim 1 , wherein the amount of the first organic solvent per 1 g of the benzylhydrazine derivative represented by formula (II) is 3 mL or more and 16 mL or less.

4. The method according to claim 1 , wherein the first separated liquid is a saline solution or water.

5. The method of claim 1 , wherein the hydrazine compound comprises hydrazine monohydrate.

6. The method according to claim 1, wherein the amount of the hydrazine compound relative to 1 mole of the benzyl derivative represented by formula (I) is 5 moles or more.

7. The method according to claim 1 , comprising contacting the benzyl derivative represented by formula (I) with the hydrazine compound in the presence of the first organic solvent to obtain the first mixture.

8. 2. The method according to claim 1, comprising: contacting the benzyl derivative represented by formula (I) with the hydrazine compound in the presence of a third organic solvent to obtain a second mixture; and mixing the second mixture with the first organic solvent to obtain the first mixture.

9. The method according to claim 8, wherein the third organic solvent comprises at least one compound selected from the group consisting of ethanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1-propanol, 2-propanol, t-butanol, and tetrahydrofuran.

10. A method for producing a pyrazole derivative, comprising contacting the first organic layer obtained by the method according to claim 1 with a compound represented by the following formula (III) to obtain a pyrazole derivative represented by the following formula (IV): [C3] [C4] In the formula (IV), X and a have the same meanings as in formula (I).

Images