JPH07206826A - Production of 5-aminopyrazole derivative - Google Patents

Abstract

PURPOSE:To exclusively obtain a 5-aminopyrazole derivative in high selectivity and yield by using a 2-substituted taminomethylene-2-cyanoacetic acid compound as a starting substance and reacting with a hydrazine derivative. CONSTITUTION:A 5-aminopyrazole derivative of formula I can be produced by reacting a 2-substituted aminomethylene-2-cyanoacetic acid compound of formula II (R<1> is a substituted amino; R<2> is a protected carboxy) or its salt with a compound of formula III (R<3> is a lower hydroxyalkyl) or its salt. The compound of formula II used as a starting substance can be produced by reacting a compound of formula IV or its salt with a compound of formula V and a compound of formula VI (R<4> is a lower alkyl). The objective compound having excellent safety can be produced since the compound of formula II is free from skin irritation. Since the compound of formula II is producible from an inexpensive compound, this process is advantageous also from the viewpoint of cost. The compound of formula I is useful as a raw material for a cephalosporin compound known as an excellent antibiotic substance.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a 5-aminopyrazole derivative which is useful as a raw material for the production of an excellent antibiotic cephalosporin compound, and is useful in the field of pharmaceutical industry. .

[0002]

Various methods for producing 5-aminopyrazole derivatives are known, for example, US Pat. No. 2,982.
In JP 9,537, 4-ethoxycarbonyl-5-amino-1- (2 is obtained by reacting ethyl 2-ethoxymethylene-2-cyanoacetate with 2-hydrazinoethanol.
-Hydroxyethyl) pyrazole is obtained, which is then subjected to elimination reaction and decarboxylation reaction of carboxy protecting group to give 5-
A method for obtaining amino-1- (2-hydroxyethyl) pyrazole is described.

[0003]

The method described in the above-mentioned U.S. Pat.
-Ethyl cyanoacetate has skin irritation such as skin irritation, and it is dangerous to produce a pyrazole derivative by applying this method (especially, in the case of large-scale synthesis, the risk is significant. ) Therefore, it is not appropriate. Furthermore, when this method is applied, the desired 5-amino-1- (2-
Hydroxyethyl) pyrazole is a by-product 3
There was a drawback that -amino-1- (2-hydroxyethyl) pyrazole was mixed.

[0004]

The present inventors have completed the present invention by finding that the drawbacks of the above-mentioned conventional methods can be solved by using a 2-substituted aminomethylene-2-cyanoacetic acid compound as a starting material. did.

The method for producing the 5-aminopyrazole derivative of the present invention can be represented by the following reaction formula.

Process for producing 5-aminopyrazole derivative

[Chemical 10] [Wherein, R ¹ represents a substituted amino group, R ² represents a protected carboxy group, and R ³ represents a hydroxy (lower) alkyl group]

The starting compound (II) or salts thereof can be produced by the method represented by the following reaction formula.

Production method of starting compound (II)

[Chemical 11] (In the formula, R ¹ , R ² and R ³ have the same meanings as described above, and R ⁴ means a lower alkyl group.)

Suitable salts of the object compound (I) are conventional non-toxic mono- or di-salts such as formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzene. Organic acid addition salts such as sulfonate and toluenesulfonate, for example, inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate, such as arginine salt and aspartic acid. Examples thereof include salts and salts with amino acids such as glutamate.

In the above and subsequent descriptions of the present specification, preferred examples and explanations of various definitions included within the scope of the present invention will be described in detail below.

The term "lower" means 1 to 6 carbon atoms unless otherwise specified.

Suitable "lower alkyl group" includes straight chain or branched chain alkyl groups such as methyl, ethyl, propyl, butyl, t-butyl, pentyl, hexyl and the like. Among them, preferred are lower alkyl groups. Is (C ₁ -C
₄ ) More preferred alkyl groups include methyl and ethyl, respectively.

Suitable "substituted amino group" is, for example, N-methylamino, N-ethylamino, N-propylamino, N-butylamino, Nt-butylamino,
N-, such as N-pentylamino, N-hexylamino, etc.
(Lower) alkylamino groups such as N, N-dimethylamino, N-methyl-N-ethylamino, N, N-diethylamino, N, N-dipropylamino, N-propyl-N-isopropylamino, N, N-dibutylamino,
N, N-di (lower) alkylamino groups such as Nt-butyl-N-pentylamino, N, N-dihexylamino and the like;

Azepinyl such as 1H-azepinyl,
Pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, for example, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,
Triazolyl such as 2,3-triazolyl, eg 1H
-Tetrazolyl, tetrazolyl such as 2H-tetrazolyl, etc. are mentioned as examples thereof. Unsaturated 3 to 8-membered containing 1 to 4 nitrogen atoms (more preferably 5 to 7).
Member) heteromonocyclic group (provided that a bond is present on the nitrogen atom);

For example, perhydroazepinyl such as perhydro-1H-azepinyl, pyrrolidinyl, imidazolidinyl, piperidino and piperazinyl are exemplified as saturated 3 to 8 members containing 1 to 4 nitrogen atoms (more preferably 5 to 5 members). 7-membered) heteromonocyclic group (provided that there is a bond on the nitrogen atom);

For example, unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atoms such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl (provided that the bond on the nitrogen atom is a bond). Have);

For example, 7-azabicyclo [2.2.1]
A saturated condensed heterocyclic group containing 1 to 4 nitrogen atoms such as heptyl, 3-azabicyclo [3.2.2] nonanyl and the like (provided that a bond is present on the nitrogen atom);

Oxazolyl and isoxazolyl, for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, oxadiazolyl such as 1,2,5-oxadiazolyl, etc., are exemplified as 1 or 2 oxygen atoms and a nitrogen atom. Unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 3 (provided that a bond is present on the nitrogen atom);

For example, a saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as morpholino and sydnonyl (provided that on the nitrogen atom) Have a bond);

For example, unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as benzoxazolyl and benzoxadiazolyl (provided that the nitrogen atom has a bond). ;

Thiazolyl, isothiazolyl, eg
Thiodiazolyl such as 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, dihydrothiazinyl, and the like, 1 to 2 sulfur atoms And an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 3 nitrogen atoms (provided that there is a bond on the nitrogen atom);

For example, sulfur atom 1 such as thiazolidinyl
To 2 and 1 to 3 nitrogen atoms, a saturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic group (provided that a bond is present on the nitrogen atom);

For example, 1 to 2 sulfur atoms and 1 nitrogen atom such as benzothiazolyl and benzothiadiazolyl.
And saturated or unsaturated monocyclic or polycyclic heterocyclic groups such as unsaturated condensed heterocyclic groups containing 3 to 3 (provided that the bond is present on the nitrogen atom).

Of the above-mentioned "substituted amino groups", more preferred
Preferred are N, N-di (lower) alkylamino
Groups, saturated 3- to 8-membered heterocycles containing 1 to 4 nitrogen atoms
Monocyclic group, and 1 to 2 oxygen atoms and nitrogen atom
Examples include saturated 3- to 8-membered heteromonocyclic groups containing 1 to 3
And more preferably N, N-di (C ₁
-C_Four) Alkylamino groups, containing 1 to 4 nitrogen atoms
A saturated 5- to 7-membered heteromonocyclic group (provided that it is bonded to the nitrogen atom)
Have a joint) and 1 to 2 oxygen atoms and nitrogen
Saturated 5- or 6-membered heteromonocyclic group containing 1 to 3 elementary atoms
(However, having a bond on the nitrogen atom),
Also preferred are N, N-dimethylamino groups,
N, N-diethylamino group, N, N-dipropylamino
Group, 1-pyrrolidinyl group, piperidino group, 1-piperazi
Examples thereof include a nyl group and a morpholino group.

Suitable "protected carboxy group" includes esterified carboxy group, and specific examples of the ester moiety of the esterified carboxy group include, for example, methyl ester, ethyl ester,
Lower alkyl esters such as propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, hexyl ester, and 1-cyclopropylethyl ester can be mentioned. These lower alkyl esters may have a suitable substituent, and examples thereof include acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester. , Lower alkanoyloxy (lower) alkyl esters such as 1-acetoxyethyl ester, 1-propionyloxyethyl ester, 2-propionyloxyethyl ester and hexanoyloxymethyl ester, for example lower alkanesulfonyl (lower) such as 2-mesylethyl ester. ) Alkyl ester or, for example, 2-iodoethyl ester, 2,
Mention may be made of mono (or di or tri) -halo (lower) alkyl esters such as 2,2-trichloroethyl ester. Further, as the ester moiety, for example, lower alkenyl ester such as vinyl ester, allyl ester; lower alkynyl ester such as ethynyl ester, propynyl ester;
-Methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiary butyl ester Al (lower) alkyl ester which may have a suitable substituent such as benzyl ester; for example, phenyl ester, 4-chlorophenyl ester, tolyl ester, 4-tertiary butylphenyl ester, xylyl ester, mesityl ester,
Examples thereof include aryl ester which may have a suitable substituent such as cumenyl ester and the like.

[0026] Among the "protected carboxy group" described above, preferred are, include lower alkoxycarbonyl groups, as more preferable, (C ₁ -C
₄ ) An alkoxycarbonyl group is mentioned, and the most preferable one is a methoxycarbonyl group or an ethoxycarbonyl group.

Incidentally, a suitable "protected carboxy group"
Also includes an amidated carboxy group, and a preferable specific example thereof is, for example, a carbamoyl group.

Suitable “hydroxy (lower) alkyl group”
As, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, 3-hydroxypropyl, 1-
(Hydroxymethyl) ethyl, 1-hydroxybutyl,
1-hydroxymethyl-1-methylethyl, 3-hydroxypentyl, 3-hydroxy-2-ethylpropyl,
6-Hydroxyhexyl and the like can be mentioned. Among them, preferred is a hydroxy (C ₁ -C ₄ ) alkyl group, and most preferred is 2-hydroxyethyl group.

In the most preferred embodiment of the present invention, as the starting compound (II), R ¹ is a morpholino group and R ^{2 is}
Is a lower alkoxycarbonyl group, and is a production method when a compound in which R ³ is a 2-hydroxyethyl group is used as the starting compound (III).

The method for producing the 5-aminopyrazole derivative of the present invention will be described in detail below.

Method for Producing 5-Aminopyrazole Derivative Compound (I) or a salt thereof can be produced by reacting compound (II) or a salt thereof with compound (III) or a salt thereof. Suitable salts of the compounds (II) and (III) may be the same as those exemplified for the compound (I). This reaction is carried out by reacting compound (II) or a salt thereof with compound (II).
By heating I) or a salt thereof in a suitable solvent (any solvent can be used as long as it does not adversely influence the reaction, for example, water, methanol, ethanol, etc.) is heated to heated. Done. Compound (I
I) and (III) are equimolar amounts to compound (II).
Although I) is used in a slightly larger amount, it is most preferable to carry out the reaction using both compounds in equimolar amounts.

The method for producing the starting compound (II) will be described in detail below.

Production Method of Starting Compound (II) Compound (II) or a salt thereof can be produced by reacting compound (IV) or a salt thereof with compound (V) and compound (VI). Suitable salts of the compound (IV) may be the same as those exemplified for the compound (I). This reaction is
It is carried out by mixing the compound (IV) or a salt thereof with the compound (V) and the compound (VI) and heating or heating. At this time, the compound (V) and the compound (VI) may be mixed in advance, heated or heated, and then the compound (IV) or a salt thereof may be added. The obtained compound (II) can be isolated by a conventional method, but can be used for the production of the target compound (I) without isolation.

[0034]

【The invention's effect】

Raw material compound (II) used in the present invention
Are known methods (US Pat. No. 2,989,537).
No. 2-ethoxymethylene-2-cyanoacetate used in No. 1) does not cause skin irritation, and therefore the present invention can be said to be extremely safe.

Further, in the method for producing the 5-aminopyrazole derivative of the present invention, the selectivity of the ring-closing direction at the time of ring-closing in the production of compound (I) is extremely excellent, and the desired 5-amino compound (I) is obtained. It is particularly useful as an industrial production method because it is obtained in high yield and selectively (in the above-mentioned known method, it is a by-product which is a ring closed in the opposite direction.
A few percent of amino-4-protected carboxy-1-hydroxy (lower) alkylpyrazole is present. ).

Further, in the present invention, since the starting compound (II) is obtained in high purity and high yield, the compound (I
I) can be used for the production of the target compound (I) without isolation. Therefore, it can be said that it is useful as an industrial production method also in that the production of the raw material compound (II) and the subsequent production of the target compound (I) can be continuously performed.

Since the starting compound (II) can be produced from a very inexpensive compound, the present invention can be said to be advantageous in terms of cost.

The 5-aminopyrazole derivative (I) which is the target compound is useful as a raw material compound for producing a cephalosporin compound as it is, but is useful as the raw material compound by the following method. It can lead to another compound.

Step 1

[Chemical 12]

Step 2

[Chemical 13]

The reactions in these steps will be described in detail below.

Step 1 Compound (VII) or a salt thereof can be produced by subjecting compound (I) or a salt thereof to a reaction for eliminating a carboxy protecting group. Suitable salts of the compound (VII) include, in addition to those exemplified for the compound (I), a metal such as an alkali metal salt such as sodium salt and potassium salt and an alkaline earth metal salt such as calcium salt and magnesium salt. Salts, ammonium salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N-
Examples thereof include organic base salts such as dibenzylethylenediamine salt. This reaction is carried out by a conventional method such as hydrolysis. The hydrolysis is preferably carried out in the presence of a base or an acid containing a Lewis acid. Suitable bases include, for example, alkali metals such as sodium and potassium,
Alkaline earth metals such as magnesium and calcium, hydroxides or carbonates or hydrogen carbonates of these metals, for example, trialkylamines such as trimethylamine and triethylamine, picoline, 1,5-diazabicyclo [4.
3.0] Inorganic bases and organic bases such as non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene and the like. Is mentioned. Suitable acids include, for example, organic acids such as formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid and the like, for example hydrochloric acid, hydrobromic acid,
Inorganic acids such as sulfuric acid may be mentioned. For example trichloroacetic acid,
The elimination using a Lewis acid such as trihaloacetic acid such as trifluoroacetic acid is preferably carried out in the presence of a cation scavenger such as anisole and phenol. The reaction is usually carried out in a conventional solvent such as water, an alcohol such as methanol and ethanol, methylene chloride, tetrahydrofuran, or a mixture thereof, but the reaction may be carried out in any other solvent as long as it does not adversely influence the reaction. It can be performed. Liquid bases or acids can also be used as solvents. The reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating.

Step 2 Compound (VIII) or a salt thereof is converted to compound (VI)
It can be produced by subjecting I) or a salt thereof to a decarboxylation reaction. Suitable salts of the compound (VIII) may be the same as those exemplified for the compound (I). The reaction in this step is carried out by a conventional method, for example, in a suitable solvent which does not adversely affect the reaction of benzene, toluene, pyridine, water, alcohol (eg, methanol, ethanol, etc.) or the like, or without heating. It is performed by heating. The reaction may be carried out in the presence of a base such as sodium hydroxide, potassium hydroxide, barium hydroxide.

[0045]

The present invention will be specifically described with reference to the following examples.

Production Example 1 Methyl cyanoacetate (30 g), methyl orthoformate (3
The mixture of 2.12 g) was heated to 90 ° C., and morpholine (26.38 g) was added dropwise over 1.5 hours. After the dropwise addition, the mixture was refluxed for 1 hour, then water (60 ml) was added to the reaction solution for crystallization. The precipitated crystals were filtered, and white crystals of methyl 2- (morpholinomethylene) -2-cyanoacetate (29.06) were obtained.
g) was obtained. NMR (CDCl ₃ , δ): 7.72 (1H, s), 4.05 (2H, bs), 3.78-
3.82 (4H, m), 3.78 (3H, s), 3.52 (2H, bs) MS (m / z) = 196 (M ⁺ )

Production Example 2 Ethyl cyanoacetate (30 g), ethyl orthoformate (3
9.30 g) and morpholine (23.10 g) were mixed and heated to reflux (128 ° C.). After the reflux was started for 1.5 hours, water (60 ml) was added and the mixture was cooled to 5 ° C. The precipitated crystals were collected by filtration to give ethyl 2- (morpholinomethylene) -2-cyanoacetate as white crystals (4
6.85 g). NMR (CDCl ₃ , δ): 7.71 (1H, s), 4.24 (2H, q, J = 7.1Hz),
4.05, 3.51 (each2H, bs), 3.79 (4H, t, J = 4.6Hz), 1.31
(3H, t, J = 7.1Hz) MS (m / z) = 210 (M ⁺ )

Production Example 3 A mixed solution of 2-cyanoacetamide (20 g), methyl orthoformate (25.24 g) and morpholine (20.72 g) was heated to reflux. After refluxing for 1 hour, the solvent was evaporated under reduced pressure, and the residue was crystallized from methanol-water to give white crystals of 2- (morpholinomethylene) -2-cyanoacetamide (1
6.01 g) was obtained. Furthermore, the second crystal (6.7
1 g) was obtained. NMR (CDCl ₃ , δ): 7.80 (1H, s), 5.84 (2H, bs), 3.97,
3.51 (each 2H, bs), 3.79 (4H, dd, J = 3.9 and 5.6Hz) MS (m / z) = 181 (M ⁺ )

Production Example 4 Ethyl cyanoacetate (100 g), ethyl orthoformate (1
31.01 g) was mixed, the temperature was raised to 130 ° C., and piperidine (75.27 g) was added dropwise. The reflux liquid was distilled off when the boiling point reached 80 ° C, and the internal temperature was kept at 100 ° C. After completion of dropping, the mixture was refluxed for 1 hour, the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography, and crystallized from ethyl acetate to obtain white crystals of ethyl 2- (piperidinomethylene) -2-cyanoacetate. (119.84 g). NMR (CDCl ₃ , δ): 7.70 (1H, s), 4.23 (2H, q, J = 7.1Hz),
3.95, 3.45 (each2H, bs), 1.72 (6H, bs), 1.30 (3H, t,
J = 7.1Hz) MS (m / z) = 208 (M ⁺ )

Production Example 5 By the same operation as in Production Example 4, ethyl cyanoacetate (10
0 g), ethyl orthoformate (131.01 g), and pyrrolidine (62.87 g) to give white crystals of 2- (1-pyrrolidinylmethylene) -2-cyanoacetate (67.21).
g) was obtained. NMR (CDCl ₃ , δ): 7.89 (1H, s), 4.22 (2H, q, J = 7.1Hz),
3.76 (4H, dt, J = 51.9 and 6.7Hz), 1.78-2.14 (4H,
m), 1.36 (3H, t, J = 7.1Hz) MS (m / z) = 194 (M ⁺ )

Production Example 6 Ethyl cyanoacetate (50 g), ethyl orthoformate (6
A mixed solution of 5.51 g) and anhydrous piperazine (19.04 g) was heated to reflux. After refluxing for 1 hour, the solvent was distilled off under reduced pressure, and the residue was crystallized from ethyl acetate. Brown crystals of 1,4-bis (2-ethoxycarbonyl-2-cyanovinyl) piperazine (57.54 g) were obtained. NMR (DMSO-d ₆ , δ): 7.89 (1H, s), 4.14 (4H, q, J = 7.0H
z), 3.34 (8H, s), 1.20 (3H, t, J = 7.0Hz) MS (m / z) = 332 (M ⁺ )

Production Example 7 Dimethylaminoformate dimethyl acetal (25 g) was added dropwise to ethyl cyanoacetate (23.73 g) at room temperature. After refluxing for 1 hour after dropping, the solvent was distilled off under reduced pressure.
The residue was crystallized from ethyl acetate / n-hexane to give 2-
White crystals (29.47 g) of ethyl (N, N-dimethylaminomethylene) -2-cyanoacetate were obtained. NMR (CDCl ₃ , δ): 7.70 (1H, s), 4.23 (2H, q, J = 7.1Hz),
3.38, 3.21 (each3H, s), 1.31 (3H, t, J = 7.1Hz) MS (m / z) = 168 (M ⁺ )

Production Example 8 Ethyl cyanoacetate (100 g), ethyl orthoformate (1
The mixed solution of 31.00 g) was heated to 120 ° C., and diethylamine (65.65 g) was added dropwise over 10 minutes. After dropping 1
After refluxing for an hour, the reaction solution was concentrated. Ethyl acetate (300
ml) and city water (300 ml) and then washed with ethyl acetate layer and saturated saline (300 ml). The organic layer is concentrated and the precipitated diethylamine hydrochloride is filtered off. By purifying the filtrate by silica gel column chromatography, 2- (N, N-diethylaminomethylene) -2-
White crystals of ethyl cyanoacetate (66.48 g) were obtained. NMR (CDCl ₃ , δ): 7.72 (1H, s), 4.23 (2H, q, J = 7.1Hz),
3.56 (4H, dq, J = 66.4,7.2Hz), 1.27-1.37 (9H, m)

Production Example 9 Ethyl cyanoacetate (50 g), ethyl orthoformate (6
A mixed solution of 5.51 g) and dipropylamine (44.73 g) was heated to reflux. The reflux liquid was distilled off when the internal temperature was 110 ° C or lower, and the internal temperature was maintained at 110 ° C or higher. After refluxing for 3 hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. 2- (N, N-dipropylaminomethylene) -2 as a pale yellow oil
-Ethyl cyanoacetate (65.02g) was obtained. NMR (CDCl ₃ , δ): 7.70 (1H, s), 4.24 (2H, q, J = 7.2Hz),
3.44 (4H, dt, J = 61.0,7.1Hz), 1.59-1.84 (4H, m), 1.22
-1.34 (3H, m), 0.85-1.03 (6H, m) MS (m / z) = 224 (M ⁺ )

Example 1 Methyl 2- (morpholinomethylene) -2-cyanoacetate (20 g) was suspended in city water (60 ml) and 95% 2-hydrazinoethanol (8.12 g) was added. The mixture was heated to reflux and the reaction was carried out at 90 to 130 ° C. while distilling off the reflux liquid. After completion of the reaction, sodium hydroxide (6.1 g) is dissolved in city water (5 ml), added to the solution containing 4-methoxycarbonyl-5-amino-1- (2-hydroxyethyl) pyrazole, and refluxed. Heated up.
After the completion of hydrolysis, the mixture was cooled and neutralized with concentrated hydrochloric acid to crystallize 4
-Carboxy-5-amino-1- (2-hydroxyethyl) pyrazole pale yellow crystals (14.93 g) (85.
6%) was obtained. NMR (DMSO-d ₆ , δ): 7.42 (1H, s), 6.07 (2H, s), 4.93
(1H, s), 3.94 (2H, t, J = 4.6Hz), 3.67 (2H, t, J = 4.6Hz),
3.36 (1H, s)

Example 2 In the same manner as in Example 1, 2- (morpholinomethylene)-
From ethyl 2-cyanoacetate and 95% 2-hydrazinoethanol, 4-ethoxycarbonyl-5-amino-1-
(2-hydroxyethyl) pyrazole is obtained, then 4
-Carboxy-5-amino-1- (2-hydroxyethyl) pyrazole was obtained. The physical properties of the compound obtained were in agreement with those of the compound obtained in Example 1.

Example 3 In the same manner as in Example 1, 2- (morpholinomethylene)-
From 2-cyanoacetamide and 95% 2-hydrazinoethanol, 4-carbamoyl-5-amino-1- (2
-Hydroxyethyl) pyrazole is obtained, then 4-carboxy-5-amino-1- (2-hydroxyethyl)
Pyrazole was obtained. The physical properties of the obtained compound are shown in Example 1.
It was identical to that of the compound obtained in.

Example 4 In the same manner as in Example 1, 2- (piperidinomethylene)-
From ethyl 2-cyanoacetate and 95% 2-hydrazinoethanol, 4-ethoxycarbonyl-5-amino-1-
(2-hydroxyethyl) pyrazole is obtained, then 4
-Carboxy-5-amino-1- (2-hydroxyethyl) pyrazole was obtained. The physical properties of the compound obtained were in agreement with those of the compound obtained in Example 1.

Example 5 In the same manner as in Example 1, 4-ethoxycarbonyl-5-amino-1 was obtained from ethyl 2- (1-pyrrolidinylmethylene) -2-cyanoacetate and 95% 2-hydrazinoethanol. -(2-Hydroxyethyl) pyrazole was obtained, followed by 4-carboxy-5-amino-1- (2-hydroxyethyl) pyrazole. The physical properties of the compound obtained were in agreement with those of the compound obtained in Example 1.

Example 6 In the same manner as in Example 1, 1,4-bis (2-ethoxycarbonyl-2-cyanovinyl) piperazine and 95% 2
From 4-hydrazinoethanol, 4-ethoxycarbonyl-5-amino-1- (2-hydroxyethyl) pyrazole is obtained, then 4-carboxy-5-amino-1-
(2-Hydroxyethyl) pyrazole was obtained. The physical properties of the compound obtained were in agreement with those of the compound obtained in Example 1.

Example 7 In the same manner as in Example 1, ethyl 2- (N, N-dimethylaminomethylene) -2-cyanoacetate and 95% 2-hydrazinoethanol were used to prepare 4-ethoxycarbonyl-5-.
Amino-1- (2-hydroxyethyl) pyrazole is obtained, then 4-carboxy-5-amino-1- (2-
Hydroxyethyl) pyrazole was obtained. The physical properties of the compound obtained were in agreement with those of the compound obtained in Example 1.

Example 8 In the same manner as in Example 1, ethyl 2- (N, N-diethylaminomethylene) -2-cyanoacetate and 95% 2-hydrazinoethanol were used to prepare 4-ethoxycarbonyl-5-.
Amino-1- (2-hydroxyethyl) pyrazole is obtained, then 4-carboxy-5-amino-1- (2-
Hydroxyethyl) pyrazole was obtained. The physical properties of the compound obtained were in agreement with those of the compound obtained in Example 1.

Example 9 Ethyl 2- (morpholinomethylene) -2-cyanoacetate (20 g) was suspended in city water (60 ml) and 95% 2-hydrazinoethanol (7.62 g) was added. The mixture was heated to reflux and the reaction was carried out at 90 to 130 ° C. while distilling off the reflux liquid. After completion of the reaction, sodium hydroxide (5.71 g) is dissolved in city water (5 ml), added to the solution containing 4-ethoxycarbonyl-5-amino-1- (2-hydroxyethyl) pyrazole, and refluxed. Heated up. After completion of hydrolysis, the mixture was cooled and neutralized with concentrated hydrochloric acid for crystallization to give 4-carboxy-5-amino-1- (2-hydroxyethyl) pyrazole as pale yellow crystals (14.27 g) (8
7.6%). NMR (DMSO-d ₆ , δ): 7.42 (1H, s), 6.07 (2H, s), 4.93
(1H, s), 3.94 (2H, t, J = 4.6Hz), 3.67 (2H, t, J = 4.6Hz),
3.36 (1H, s)

Reference Example 1 4-Carboxy-5-amino-1- (2-hydroxyethyl) pyrazole (40 g) was added to toluene (120 ml).
And heat to reflux. When the crystals are dissolved and the reaction is completed, the mixture is cooled and methanol (20 ml) is added for crystallization. The crystals were filtered and pale yellow crystals of 5-amino-1- (2-hydroxyethyl) pyrazole (27.33 g) (9
1.9%). NMR (DMSO-d ₆ , δ): 7.03 (1H, d, J = 1.8Hz), 5.26 (1H,
d, J = 1.8Hz), 5.06 (2H, s), 4.95 (1H, t, J = 5.2Hz), 3.90
(2H, t, J = 6.0Hz), 3.63 (2H, dt, J = 6.0 and 5.4Hz)

Claims (2)

[Claims] 1. A general formula: (Wherein R ¹ represents a substituted amino group, and R ² represents a protected carboxy group, respectively) and a compound (II) represented by the general formula: [Wherein R ³ represents a hydroxy (lower) alkyl group] is reacted with a compound (III) represented by the formula: A method for producing a 5-aminopyrazole derivative, which comprises obtaining the compound (I) represented by the formula (wherein R ² and R ³ have the same meanings as described above) or salts thereof. 2. A general formula: (Wherein R ¹ has the same meaning as described above) (I
V) or a salt thereof and a compound represented by the general formula: (In the formula, R ² has the same meaning as described above), and a compound of formula (V) (Wherein R ⁴ represents a lower alkyl group) is reacted to give a compound of the general formula: (Wherein each of R ¹ and R ² has the same meaning as described above), and a compound (II) or a salt thereof is obtained. Further, the obtained compound (II) or a salt thereof and a compound represented by the general formula: (Wherein R ³ has the same meaning as described above) (II
I) or a salt thereof is reacted to give a compound of the general formula: A method for producing a 5-aminopyrazole derivative, which comprises obtaining the compound (I) represented by the formula (wherein R ² and R ³ have the same meanings as described above) or salts thereof.