JP2003155275A - Method for producing 5-amino-4-nitrosopyrazole derivative or its salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a 5-amino-4-nitrosopyrazole derivative or its salt at a high yield by a simple method from an easily available raw material. SOLUTION: This method for producing a 5-amino-4-nitrosopyrazole derivative represented by the general formula (3) [wherein, R<3> is H or (substituted) alkyl or aryl] or its salt is characterized by reacting 3,3-dialkoxy-2- hyhdroxyiminopropionitrile represented by the general formula (1) (wherein, R<1> and R<2> are the same or different 1-8C alkyl) with a hydrazine compound represented by the general formula (2) H2 NNHR<3> (2) [wherein, R<3> is H or (substituted) alkyl or aryl].

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a 5-amino-4-nitrosopyrazole derivative or an acid salt thereof, which is useful as an intermediate for pharmaceuticals, agricultural chemicals and the like. A 5-amino-4-nitrosopyrazole derivative can be used as a raw material for synthesizing a 4,5-diaminopyrazole derivative useful as a hair dye or an intermediate of an antitumor agent (for example, JP-A-60-56981,
JP-A-62-273979, JP-T-Hei 7-502542). 2. Description of the Related Art Conventionally, a method for producing a 5-amino-4-nitrosopyrazole derivative or an acid salt thereof is disclosed in, for example,
-273979, in the presence of hydrogen chloride, 5-amino-1- (2-
There is disclosed a method for reacting isoamyl nitrite with (hydroxyethyl) -pyrazole to obtain 5-amino-1- (2-hydroxyethyl) -4-nitrosopyrazole hydrochloride. However, in this method, the reaction operation is complicated, and
There was a problem that the yield of the target product was low. [0003] The object of the present invention is to provide a desired 5-amino-4-nitrosopyrazole derivative or its derivative from a readily available raw material in a high yield by a simple method. The present invention provides a method for producing an acid salt. [0004] The object of the present invention is to provide a compound of the general formula (1) in the presence of an acid. (Wherein, R ¹ and R ² may be the same or different and each represent an alkyl group having 1 to 8 carbon atoms.) 3,3-dialkoxy-2-hydroxyiminopro Pionitrile has the general formula (2) Wherein R ³ represents a hydrogen atom, an alkyl group or an aryl group which may have a substituent, and a hydrazine compound represented by the following general formula (3): [0009] (In the formula, R ³ has the same meaning as described above.) This is solved by a method for producing a 5-amino-4-nitrosopyrazole derivative or an acid salt thereof. BEST MODE FOR CARRYING OUT THE INVENTION Used in the reaction of the present invention
3,3-dialkoxy-2-hydroxyiminopropionitrile is represented by the above general formula (1). In the general formula (1), R ¹ and R ² may be the same or different and represent an alkyl group having 1 to 8 carbon atoms.
Examples include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, and an octyl group, and preferably a methyl group and a butyl group. These groups include various isomers. The 3,3-dialkoxy-2-hydroxyiminopropionitrile is, for example, a compound represented by the general formula (4): (Wherein, R ¹ and R ² have the same meanings as described above, and X represents a halogen atom).
It can be easily synthesized by reacting a nitrosyl halide with an enol ether compound in the presence of an alcohol. Since 3,3-dialkoxy-2-hydroxyiminopropionitrile has an oxime group, there are several isomers such as E-form and Z-form, but any isomer is included. The hydrazine compound used in the reaction of the present invention is represented by the above general formula (2). In the general formula (2), R ³ represents a hydrogen atom, an alkyl group or an aryl group which may have a substituent. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, and a heptyl group.Examples of the aryl group include:
Phenyl group, naphthyl group, pyridyl group, pyrimidyl group,
Examples include a pyrazyl group, a pyridazyl group, and a quinolyl group. These groups include various isomers. Examples of the substituent include a hydroxyl group; an alkyl group such as a methyl group, an ethyl group, a propyl group, and a butyl group (these groups include various isomers); a methoxyl group, an ethoxyl group, and a propoxy group. And aryl groups such as phenyl, thienyl, furyl, pyridyl, and pyrimidyl; fluorine, chlorine, and bromine. And a halogen atom such as an iodine atom; and a nitro group. The position and number of the substituent are not particularly limited. The amount of the hydrazine compound used is 1 mol of 3,3-dialkoxy-2-hydroxyiminopropionitrile.
Preferably 0.5 to 2.0 mol, more preferably 0.7 mol
1.51.5 mol. The acid used in the reaction of the present invention includes, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid,
Mineral acids such as hydroiodic acid; organic carboxylic acids such as acetic acid and propionic acid; organic sulfonic acids such as methanesulfonic acid and benzenesulfonic acid; aluminum chloride, zinc chloride;
Examples thereof include Lewis acids such as titanium tetrachloride and boron trifluoride, preferably mineral acids, more preferably hydrochloric acid and sulfuric acid. In addition, you may use these acids individually or in mixture of 2 or more types. The amount of the acid used is 3,3-dialkoxy-2-
It is preferably 0.1 to 20 mol, more preferably 0.8 to 5 mol, per 1 mol of hydroxyiminopropionitrile. The reaction of the present invention is carried out in the presence or absence of a solvent. When a solvent is used, it is not particularly limited as long as it does not inhibit the reaction. For example, water; methanol, ethanol, n Alcohols such as -propyl alcohol, isopropyl alcohol, n-butyl alcohol and t-butyl alcohol; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; Aliphatic hydrocarbons such as pentane, hexane, heptane and cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; acetonitrile and propio Nitriles such as nitriles; carboxylic acids such as acetic acid and propionic acid Emissions acids; ethyl acetate, butyl acetate, although esters such as ethyl propionate and the like, preferably an alcohol, more preferably methanol, ethanol, isopropyl alcohol is used. These solvents may be used alone or in combination of two or more. The amount of the solvent to be used is appropriately adjusted depending on the uniformity and stirring properties of the reaction solution, but is preferably 1 g of 3,3-dialkoxy-2-hydroxyiminopropionitrile.
It is 0-100 g, more preferably 0-30 g. The reaction of the present invention is carried out by, for example, mixing an acid, 3,3-dialkoxy-2-hydroxyiminopropionitrile, a hydrazine compound and a solvent and stirring the mixture. The reaction temperature at that time is preferably -20 to 1
The temperature is 50 ° C, more preferably 0 to 90 ° C, and the reaction pressure is not particularly limited. The reaction of the present invention gives an acid salt of a 5-amino-4-nitrosopyrazole derivative, which can be obtained as a free 5-amino-4-nitrosopyrazole derivative by neutralization with a base. I can do it. The 5-amino-4-nitrosopyrazole derivative or an acid salt thereof can be isolated and purified by a general method such as crystallization, recrystallization, concentration, and column chromatography. Next, the present invention will be described specifically with reference to examples, but the scope of the present invention is not limited to these examples. Reference Example 1 (Synthesis of 3,3-dimethoxy-2-hydroxyiminopropionitrile) A 300-ml flask equipped with a stirrer, a thermometer, a cooler, and a gas inlet was charged with 97% by mass of purity. 42.83 g (0.5 mol) of 3-methoxyacrylonitrile and 125 ml of methanol were added, and the mixture was cooled to −10 ° C. with stirring. Next, the reaction solution was maintained at -10 to 0 ° C, and nitrosyl chloride generated by reacting 170.5 g (1.0 mol) of a 41% by mass aqueous sodium nitrite solution with 320 ml (3.5 mol) of concentrated hydrochloric acid in a separate container was reacted. While supplying the solution, the reaction was carried out at -10 to 0 ° C for 3 hours and at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrate was n-
Washed in the order of hexane and toluene, dried at 40 ° C under reduced pressure, and 3,3-dimethoxy-2 having a purity of 93.7% by mass (absolute calibration curve method by high performance liquid chromatography) as a pale yellow solid.
61.6 g of -hydroxyiminopropionitrile was obtained (isolation yield: 80.1%). Example 1 (Synthesis of 5-amino-1- (2-hydroxyethyl) -4-nitrosopyrazole hydrochloride) An inner volume of 100 ml equipped with a stirrer, a thermometer and a reflux condenser.
In a flask having a purity of 9 synthesized in the same manner as in Reference Example 1.
8.43 g (55 mmol) of 4.0% by mass of 3,3-dimethoxy-2-hydroxyiminopropionitrile, 4.01 g (50 mmol) of 2-hydroxyethylhydrazine having a purity of 95% by mass, 50 ml of ethanol and 7.60 g (75 mmol) of concentrated hydrochloric acid were added. Add under reflux (76-79 ° C)
Allowed to react for hours. After completion of the reaction, the reaction solution is concentrated under reduced pressure, and the concentrate is mixed with 20 ml of toluene and isopropyl alcohol.
20 ml was added, and the mixture was stirred at room temperature for 1 hour. Next, this solution was filtered, and the filtrate was dried under reduced pressure at 40 ° C., and as a yellow solid, the purity was 94.8% by mass (absolute calibration method by high performance liquid chromatography). 5-amino-1- (2-hydroxyethyl)-
6.85 g of 4-nitrosopyrazole hydrochloride was obtained (isolation yield: 6
7.4%). The physical properties of 5-amino-1- (2-hydroxyethyl) -4-nitrosopyrazole hydrochloride were as follows. Melting point: 164.8-166.6 ° C. (dec.) ¹ H-NMR (DMSO-d ₆ , δ (ppm)); 3.65-4.13 (4H, m), 6.80
10.40 (5H, m) IR (KBr method, cm ^-1 ); 3290, 3063, 2635, 1670, 1623, 120
8, 1099, 1063, 1002, 716 Example 2 (Synthesis of 5-amino-1- (2-hydroxyethyl) -4-nitrosopyrazole hydrochloride) A stirrer, a thermometer and a reflux condenser were provided. Purity 98.1 synthesized in the same manner as in Reference Example 1 in a flask having an inner volume of 25 ml.
1.47 g (10.0 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile by mass%, 0.84 g (10.5 mmol) of 2-hydroxyethylhydrazine having a purity of 95 mass%, methanol 10 ml
And 1.5 ml (18.0 mmol) of concentrated hydrochloric acid, and the mixture was refluxed (67 ° C.).
For 1.5 hours. After the completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute calibration curve method). As a result, 1.81 g of 5-amino-1- (2-hydroxyethyl) -4-nitrosopyrazole hydrochloride was produced (reaction Yield: 93.8
%). Example 3 (Synthesis of 5-amino-1- (2-hydroxyethyl) -4-nitrosopyrazole hydrogen sulfate) A 25-ml flask equipped with a stirrer, a thermometer and a reflux condenser was used as a reference. Purity 98.1 synthesized in the same manner as in Example 1.
1.47 g (10.0 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile by mass%, 0.84 g (10.5 mmol) of 2-hydroxyethylhydrazine having a purity of 95 mass%, water 0.54 ml, methanol 10 ml and concentrated sulfuric acid 1.18 g (12.0 mmol) was added and reacted under reflux (66-67 ° C) for 3 hours. After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute calibration curve method), and it was found that 5-amino-1- (2-hydroxyethyl)-
2.24 g of 4-nitrosopyrazole hydrogen sulfate was produced
(Reaction yield: 88.2%). Example 4 (Synthesis of 5-amino-1- (2-hydroxyethyl) -4-nitrosopyrazole hydrochloride) 200 ml in internal volume equipped with a stirrer, thermometer and reflux condenser
In a flask having a purity of 9 synthesized in the same manner as in Reference Example 1.
16.86 g (110 mmol) of 4.0% by mass of 3,3-dimethoxy-2-hydroxyiminopropionitrile, 8.02 g (100 mmol) of 2-hydroxyethylhydrazine having a purity of 95% by mass, and ethanol 100 m
l and concentrated hydrochloric acid 10 ml (120 mmol) are added, and the mixture is refluxed (76-77 ° C).
For 1 hour. After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute calibration curve method), and it was found that 17.62 g of 5-amino-1- (2-hydroxyethyl) -4-nitrosopyrazole hydrochloride was produced (reaction Yield: 91.5
%). Example 5 (Synthesis of 5-amino-1- (2-hydroxyethyl) -4-nitrosopyrazole hydrochloride) In a 25-ml flask equipped with a stirrer, a thermometer and a reflux condenser, the reference example was prepared. Purity 94.0 synthesized by the same method as 1.
3.37 g (22 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile by mass%, 1.60 g (20 mmol) of 2-hydroxyethylhydrazine having a purity of 95 mass%, 9.6 ml of isopropyl alcohol and 2 ml (24 mmol) of concentrated hydrochloric acid. In addition, under reflux (79 ~
(80 ° C) for 1 hour. After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute calibration curve method). As a result, 3.35 g of 5-amino-1- (2-hydroxyethyl) -4-nitrosopyrazole hydrochloride was produced (reaction Yield: 8
6.9%). Example 6 (Synthesis of 5-amino-1- (2-hydroxyethyl) -4-nitrosopyrazole) A 25-ml flask equipped with a stirrer and a thermometer was charged with
2.10 g (10 mmol) of 5-amino-1- (2-hydroxyethyl) -4-nitrosopyrazole hydrochloride synthesized in the same manner as in Example 1 and having a purity of 91.6% by mass, 3.5 ml of water and 0.5 ml of isopropyl alcohol were added. Was. Next, 1 ml of 28% ammonia water (16 mmo
l) is slowly added dropwise while maintaining the liquid temperature at 5 ° C or less.
Allowed to react for minutes. After the completion of the reaction, the precipitated crystals were filtered. Next, the crystals were washed with 1 ml of cold water and 1 ml of cooled isopropyl alcohol, and dried at 40 ° C. under reduced pressure to give 5-amino-purified 99.7% by mass (absolute calibration curve method by high performance liquid chromatography) as red-orange crystals. -1-
1.13 g of (2-hydroxyethyl) -4-nitrosopyrazole was obtained (isolation yield: 72.0%). The physical properties of 5-amino-1- (2-hydroxyethyl) -4-nitrosopyrazole were as follows. Melting point: 170.2-171.8 ° C. (dec.) ¹ H-NMR (DMSO-d ₆ , δ (ppm)): 3.60-4.03 (4H, m), 4.75-
5.03 (1H, br), 7.06 (0.16H, s), 7.76 ~ 8.29 (2H, br), 8.5
3 (0.84H, s) IR (KBr method, cm ^-1 ); 3346, 3168, 2960, 1658, 1529, 149
7,1243,1072,1016,913,624 Example 7 (Synthesis of 5-amino-1- (2-hydroxyethyl) -4-nitrosopyrazole) A stirrer, a thermometer and a reflux condenser were provided. In a flask having an inner volume of 50 ml, a purity of 94.3 synthesized in the same manner as in Reference Example 1.
4.59 g (30 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile by mass%, 2.98 g (31.5 mmol) of 2-hydroxyethylhydrazine having a purity of 80.5 mass%, 7.8 ml of methanol
And 4.5 ml (54 mmol) of concentrated hydrochloric acid, and reacted at 50 to 52 ° C. for 3 hours. After the reaction was completed, 7 ml of water was added and the mixture was cooled to 10 ° C, and 3.5 ml (58 mmol) of 28% by mass aqueous ammonia was slowly added dropwise, followed by stirring for 30 minutes while keeping the liquid temperature at 5 ° C or lower. The precipitated crystals were filtered, and then the crystals were cooled in cold water 2.
After washing with 5 ml and cooled methanol (2.5 ml), the residue was dried under reduced pressure to give 5-amino-1- (2-hydroxyethyl) having a purity of 96.0% by mass (absolute calibration method by high performance liquid chromatography) as red-orange crystals. ) -4-Nitrosopyrazole 3.
40 g were obtained (isolation yield: 69.7%). Example 8 (Synthesis of 5-amino-1-methyl-4-nitrosopyrazole) In a 25 ml-volume flask equipped with a stirrer, a thermometer and a reflux condenser, 3,3-purity of 96.9% by mass was prepared. 2.97 g (20 mmol) of dimethoxy-2-hydroxyiminopropionitrile, purity 97
1.01 g (21 mmol) of methylhydrazine,
ml and concentrated hydrochloric acid (3.0 ml, 36 mmol) were added, and the mixture was reacted at 50 to 52 ° C for 4 hours. After completion of the reaction, 5 ml of water was added and the mixture was cooled to 10 ° C., and then 2.3 ml (37.9 mmol) of 28% by mass aqueous ammonia was slowly added dropwise, followed by stirring for 30 minutes while keeping the liquid temperature at 5 ° C. or lower. The precipitated crystals are filtered, and then the crystals are cooled with cold water.
After washing with 1.2 ml and cooled methanol 1.2 ml, dried under reduced pressure to a purity of 98.8% by mass as a dark purple solid
(Absolute calibration curve method by high performance liquid chromatography)
1.91 g of 5-amino-1-methyl-4-nitrosopyrazole was obtained (isolation yield: 74.8%). The physical properties of 5-amino-1-methyl-4-nitrosopyrazole were as follows. [0035] ^{1 H-NMR (DMSO-d} 6, δ (ppm)); 3.51 (2.4H,
s), 3.58 (0.6H, s), 7.02 (0.2H, s), 7.85 to 8.20 (2H, b
r), 8.51 (0.8 H, s) IR (KBr method, cm ^-1 ); 3369, 3173, 1648, 1524, 1424, 129
6, 1187, 1007, 937, 830, 562 Example 9 (Synthesis of 5-amino-1-t-butyl-4-nitrosopyrazole) 25 ml of internal volume equipped with a stirrer, thermometer and reflux condenser In a flask having a purity of 96.9 synthesized in the same manner as in Reference Example 1,
2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile by mass%, 2.70 g (21 mmol) of t-butylhydrazine hydrochloride having a purity of 97 mass%, 1.4 ml of water, and 6 ml of methanol
And 1.3 ml (15 mmol) of concentrated hydrochloric acid, and reacted at 60 to 62 ° C. for 3 hours. After completion of the reaction, 5 ml of water was added and the mixture was cooled to 10 ° C., and then 2.3 ml (37.9 mmol) of 28% by mass aqueous ammonia was slowly added dropwise, followed by stirring for 30 minutes while keeping the liquid temperature at 5 ° C. or lower. The precipitated crystals were filtered, and then the crystals were cooled in cold water 1.
After washing with 2 ml and cooled methanol 1.2 ml, it was dried under reduced pressure to give 5-amino-1-t-butyl-4 having a purity of 96.2% by mass (absolute calibration method by high performance liquid chromatography) as a red-orange solid. 1.93 g of -nitrosopyrazole was obtained (isolation yield: 55.2%). The physical properties of 5-amino-1-t-butyl-4-nitrosopyrazole were as follows. ¹ H-NMR (DMSO-d ₆ , δ (ppm)); 1.53 (7.2 H,
s), 1.58 (1.8H, s), 6.99 (0.2H, s), 7.80-8.30 (2H, b
r), 8.48 (0.8H, s) IR (KBr method, cm ^-1 ); 3345, 3160, 2983, 1632, 1524, 147
8, 1238, 1079, 835, 607 Example 10 (Synthesis of 5-amino-1-benzyl-4-nitrosopyrazole) A 25-ml flask equipped with a stirrer, a thermometer and a reflux condenser was placed in a flask. Purity 96.9 synthesized in the same manner as in Reference Example 1.
2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile by mass%, 4.22 g (21 mmol) of benzylhydrazine hydrochloride having a purity of 97 mass%, 1.4 ml of water, and 6 ml of methanol
And 1.3 ml (15 mmol) of concentrated hydrochloric acid, and reacted at 50 to 52 ° C. for 3 hours. After completion of the reaction, 5 ml of water was added and the mixture was cooled to 10 ° C., and then 2.3 ml (37.9 mmol) of 28% by mass aqueous ammonia was slowly added dropwise, followed by stirring for 30 minutes while keeping the liquid temperature at 5 ° C. or lower. The precipitated crystals are filtered, and then the crystals are
After washing with l, drying under reduced pressure gave 3.89 g of 5-amino-1-benzyl-4-nitrosopyrazole having a purity of 86.1% by mass (absolute calibration method by high performance liquid chromatography) as a brown solid ( Isolation yield: 82.8%). The physical properties of 5-amino-1-benzyl-4-nitrosopyrazole were as follows. ¹ H-NMR (DMSO-d ₆ , δ (ppm)); 5.16 (1.5 H,
s), 5.23 (0.5H, s), 7.04-7.53 (5.25H, m), 8.25-8.50
(2H, br), 8.59 (0.75H, s) IR (KBr method, cm ^-1 ); 3354, 3160, 3033, 1647, 1523, 148
8, 1453, 1254, 1219, 1055, 957, 836, 699 Example 11 (Synthesis of 5-amino-4-nitroso-1-phenylpyrazole) Contents equipped with a stirrer, thermometer and reflux condenser In a 25 ml flask, a purity of 96.9 was synthesized in the same manner as in Reference Example 1.
2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile by mass%, 2.32 g (21 mmol) of phenylhydrazine having a purity of 98 mass%, 10 ml of methanol and 3.0 ml of concentrated hydrochloric acid
(36 mmol) was added and reacted at 50-52 ° C for 1 hour. After completion of the reaction, 10 ml of water was added and the mixture was cooled to 10 ° C., and then 2.3 ml (37.9 mmol) of 28% by mass aqueous ammonia was slowly added dropwise, and the mixture was stirred for 30 minutes while keeping the liquid temperature at 5 ° C. or lower. The precipitated crystals were filtered, and the crystals were washed with 5 ml of cold water and dried under reduced pressure to give 5-amino-purity of 74.9% by mass (absolute calibration method by high performance liquid chromatography) as an ocher solid. 4-nitroso-1-phenylpyrazole 3.19
g was obtained (isolation yield: 63.4%). The physical properties of 5-amino-4-nitroso-1-phenylpyrazole were as follows. ¹ H-NMR (DMSO-d ₆ , δ (ppm)); 6.83 to 7.31 (5
H, m), 7.69 (0.5H, d), 8.00 (0.5H, d), 11.00 (0.5H, s), 1
1.29 (0.5H, s), 12.80 to 13.75 (1H, br) IR (KBr method, cm ^-1 ); 3279, 2255, 1605, 1559, 1495, 126
2,1170,1002,876,754,689,621,504 Example 12 (Synthesis of 5-amino-1- (4-methylphenyl) -4-nitrosopyrazole) Stirrer, thermometer and reflux cooling A flask having an inner volume of 25 ml and a vessel having a purity of 96.9 was synthesized in the same manner as in Reference Example 1.
2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile by mass%, 3.40 g (21 mmol) of 4-methylphenylhydrazine hydrochloride having a purity of 98 mass%, 1.4 ml of water, 10 ml of methanol and 1.3 ml of concentrated hydrochloric acid ml (15 mmol) and at 50-52 ° C 1
Allowed to react for hours. After completion of the reaction, water 15 ml and methanol 5 ml
After cooling to 10 ° C, 28% by mass aqueous ammonia 2.
3 ml (37.9 mmol) was slowly added dropwise, and the mixture was stirred for 30 minutes while keeping the liquid temperature at 5 ° C or lower. The precipitated crystals were collected by filtration, washed with 15 ml of cold water, and dried under reduced pressure to give 5-amino-1 having a purity of 83.5% by mass (absolute calibration curve method by high performance liquid chromatography) as a yellow solid. -
3.26 g of (4-methylphenyl) -4-nitrosopyrazole was obtained.
(Isolation yield: 67.3%). The physical properties of 5-amino-1- (4-methylphenyl) -4-nitrosopyrazole were as follows. [0043] ^{1 H-NMR (DMSO-d} 6, δ (ppm)); 2.22 (1.35H,
s), 2.24 (1.65H, s), 6.93 to 7.13 (4H, m), 7.66 (0.45H,
s), 7.96 (0.55H, d), 10.91 (0.45H, s), 11.22 (0.55H, d)
s), 12.70 to 13.70 (1H, br) IR (KBr method, cm ^-1 ); 3281, 3255, 2258, 1616, 1550, 150
7, 1258, 1177, 1025, 872, 811, 506 Example 13 (Synthesis of 5-amino-1- (4-chlorophenyl) -4-nitrosopyrazole) A stirrer, a thermometer and a reflux condenser were provided. In a flask having an internal volume of 25 ml, 96.9 was synthesized in the same manner as in Reference Example 1.
2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile by mass%, 3.96 g (21 mmol) of 4-chlorophenylhydrazine hydrochloride having a purity of 95 mass%, 1.4 ml of water, 10 ml of methanol and 1.3 ml of concentrated hydrochloric acid (15 mmol) and 2 at 50-52 ° C.
Allowed to react for hours. After the reaction, 25 ml of water and 5 ml of methanol
After cooling to 10 ° C, 28% by mass aqueous ammonia 2.
3 ml (37.9 mmol) was slowly added dropwise, and the mixture was stirred for 30 minutes while keeping the liquid temperature at 5 ° C or lower. The precipitated crystals were filtered, washed with 10 ml of cold water, and dried under reduced pressure to give 5-amino-1 having a purity of 88.7% by mass (absolute calibration curve method by high performance liquid chromatography) as a yellow solid. -
3.73 g of (4-chlorophenyl) -4-nitrosopyrazole was obtained.
(Isolation yield: 74.3%). The physical properties of 5-amino-1- (4-chlorophenyl) -4-nitrosopyrazole were as follows. ¹ H-NMR (DMSO-d ₆ , δ (ppm)); 7.02 to 7.38 (4
H, m), 7.70 (0.45H, s), 8.01 (0.55H, s), 11.10 (0.45H,
s), 11.38 (0.55H, s), 12.90 to 13.80 (1H, br) IR (KBr method, cm- ¹ ); 3267, 2254, 1604, 1550, 1489, 125
5,1171,1090,1007,875,825,507 Example 14 (Synthesis of 5-amino-1- (4-methoxyphenyl) -4-nitrosopyrazole) A stirrer, thermometer and reflux condenser were used. A flask having an internal volume of 25 ml was prepared in the same manner as in Reference Example 1 and had a purity of 96.9.
2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile by mass, 3.74 g (21 mmol) of 4-methoxyphenylhydrazine hydrochloride having a purity of 98 mass%, 1.4 ml of water, 10 ml of methanol and 1.3 ml of concentrated hydrochloric acid Add ml (15 mmol), 50-52 ° C
For 1 hour. After the reaction, 25 ml of water and 5 ml of methanol
After cooling to 10 ° C, 28% by mass aqueous ammonia
2.3 ml (37.9 mmol) was slowly added dropwise, and the mixture was stirred for 30 minutes while keeping the liquid temperature at 5 ° C or lower. The precipitated crystals are filtered,
Next, the crystals were washed with 10 ml of cold water, and then dried under reduced pressure to give 5-amino-1 having a purity of 78.6% by mass (absolute calibration curve method using high performance liquid chromatography) as a yellow solid.
3.07 g of-(4-methoxyphenyl) -4-nitrosopyrazole was obtained (isolation yield: 55.3%). The physical properties of 5-amino-1- (4-methoxyphenyl) -4-nitrosopyrazole were as follows. ¹ H-NMR (DMSO-d ₆ , δ (ppm)); 3.70 (1.35 H,
s), 3.71 (1.65H, s), 6.86-7.07 (4H, m), 7.63 (0.45H,
d), 7.93 (0.55H, d), 10.87 (0.45H, s), 11.19 (0.55H,
s), 12.70 to 13.50 (1H, br) IR (KBr method, cm ^-1 ); 3305, 3013, 2264, 1552, 1515, 146
5, 1227, 1174, 1008, 832, 571, 525 According to the present invention, the desired 5-amino-4-amine can be obtained in a simple process and in a high yield from easily available raw materials.
A method for producing a nitrosopyrazole derivative or an acid salt thereof can be provided.

Claims (1)

[Claim 1] In the presence of an acid, a compound represented by the general formula (1): (Wherein, R ¹ and R ² may be the same or different and represent an alkyl group having 1 to 8 carbon atoms).
3,3-dialkoxy-2-hydroxyiminopropionitrile has the general formula (2) (Wherein R ³ represents a hydrogen atom, an alkyl group or an aryl group which may have a substituent). A hydrazine compound represented by the following general formula (3): 3] (Wherein R ³ has the same meaning as described above.) A method for producing a 5-amino-4-nitrosopyrazole derivative or an acid salt thereof,