JP3152318B2 - Method for producing 5-chloro-4-nitropyrazole derivative - Google Patents

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-chloro-4-nitropyrazole derivative which is useful as an intermediate for pharmaceuticals, agricultural chemicals and the like.

[0002]

2. Description of the Related Art As a method for producing a 5-chloro-4-nitropyrazole derivative, US Pat. No. 4,077,956 describes a method of reaction formula 1. Since the method of Reaction Scheme 1 uses 5-chloropyrazoles which are unsubstituted at the 4-position on the pyrazole ring as a raw material, synthesis of the raw material may be difficult when the 3-position on the pyrazole ring is a halogen atom or a haloalkyl group. . For example, as shown in Reaction Scheme 2, 3,5-dichloro-1-methylpyrazole (a) is 3,5-dichloro-1
-Methylpyrazole-4-carboxylic acid (b) can be produced by heating and melting,
And the yield is low due to resinification during the reaction (Reference Example 1).

Also, as shown in Reaction Scheme 3, BEILSTEINS H
ANDBUCH DER ORGANISCHEN CHEMIE II, 23 , p49
A method for producing a 5-chloropyrazole (d) by heating a pyrazolone (c) with phosphorus oxychloride is described. However, when the substituent at the 3-position on the pyrazolone ring is a trifluoromethyl group, This reaction does not proceed and 5-chloro-3
-Trifluoromethyl-1-methylpyrazole (e)
Has not yet been reported in the literature (Reference Example 4).

[0004]

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[0005]

Means for Solving the Problems The present inventors have earnestly studied a method for obtaining a 5-chloro-4-nitropyrazole derivative having a halogen atom or a C _1-4 haloalkyl group at the 3-position on the pyrazole ring in good yield. As a result, the present invention has been completed. That is, the present invention relates to the formula (1):

[0006]

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[Wherein, R ¹ represents a halogen atom or a C _1-4 haloalkyl group, R ² represents a hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _2-4 alkenyl group, C
_2-4 alkynyl group, C _1-2 alkyl group substituted with C _3-6 cycloalkyl group, benzyl group, phenyl group (C _1-4
It may be substituted by one or more substituents selected from an alkyl group, a C _1-4 haloalkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, a cyano group, a nitro group and a halogen atom. ) Or a pyridyl group (C _1-4 alkyl group, C _1-4 haloalkyl group, C _1-4 alkoxy group, C
_It may be substituted by one or more substituents selected from _1-4 haloalkoxy groups, cyano groups, nitro groups and halogen atoms. ). A nitration of a 5-chloropyrazole-4-carboxylic acid derivative represented by the formula (2):

[0008]

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[Wherein R ¹ and R ² have the same meanings as described above. And a method for producing a 5-chloro-4-nitropyrazole derivative represented by the formula: In the above formulas (1) and (2), the substituents R ¹ and R ² are specifically listed as follows. However, the symbols have the following meanings.

Me: methyl group, Et: ethyl group, Pr-
n: normal propyl group, Pr-iso: isopropyl
Group, Bu-n: normal butyl group, Bu-iso: iso
Butyl group, Bu-sec: secondary-butyl group, Bu
-Tert: tertiary butyl group, Pen-n: nor
Malpentyl group, Hex-n: normal hexyl group, P
r-cyc: cyclopropyl group, Bu-cyc: cyclo
Butyl group, Pen-cyc: cyclopentyl group, Hex
-Cyc: cyclohexyl group, Ph: phenyl group, P
y: pyridyl group [substituent R¹Specific examples of F), Cl, Br, I, CH_TwoF, CH_TwoCl
 , CH_TwoBr, CH_TwoI, CHF_Two, CHCl_Two , CHBr_Two , CF_Three, CCl
_Three , CBr_Three , CClF_Two , CF_ThreeCH_Two, CF_ThreeCF_Two, CF_ThreeCF_TwoCF_Two , CF
_ThreeCF_TwoCF_TwoCF_Two [Substituent R^TwoSpecific examples of H, Me, Et, Pr-n, Pr-iso, Bu
-n, Bu-iso, Bu-sec, Bu-tert, Pen-n, Hex-n, Pr-cyc,
 Bu-cyc, Pen-cyc, Hex-cyc, CH_TwoCH = CH_2,CH_TwoCH = CHMe,
CH_TwoCH_TwoCH = CH_Two, CH _TwoC≡CH, CH_TwoC≡CMe, CH_TwoPr-cyc, CH_TwoB
u-cyc, CH_TwoPen-cyc, CH_TwoHex-cyc, CH_TwoCH_TwoPr-cyc, CH_TwoPh,
 Ph, 2-Cl-Ph, 3-Cl-Ph, 4-Cl-Ph, 2,4-Cl_Two-Ph, 2-F-P
h, 3-F-Ph, 4-F-Ph, 2-F-4-Cl-Ph, 2-Br-Ph, 3-Br-Ph, 4
-Br-Ph, 2-Me-Ph, 3-Me-Ph, 4-Me-Ph, 2,4-Me_Two-Ph, 2,6
-Me_Two-Ph, 2-MeO-Ph, 3-MeO-Ph, 4-MeO-Ph, 2-CF_Three-Ph, 3
-CF_Three-Ph, 4-CF_Three-Ph, 3,5-Cl_Two-Ph, 2,6-Cl_Two-Ph, 2,3-Cl_Two
-Ph, 2,4,6-Cl_Three-Ph, 2,3,5-Cl_Three-Ph, 2,3,4-Cl_Three-Ph, 2-C
l-4-CF_Three-Ph, 2,6-Cl_Two-4-CF_Three-Ph, 2-NO_Two-Ph, 2-CN-Ph,
2,5-Cl_Two-Ph, 3,4-Cl_Two-Ph, 2,4- (NO_Two)_Two-Ph, 3-NO_Two-Ph, 4
-NO_Two-Ph, 2-Py, 3-Py, 4-Py, 3-Cl-2-Py, 4-Cl-2-Py, 5-
Cl-2-Py, 6-Cl-2-Py, 3-F-2-Py, 4-F-2-Py, 5-F-2-Py,
6-F-2-Py, 3-Br-2-Py, 4-Br-2-Py, 5-Br-2-Py, 6-Br-2-
Py, 3-CF_Three-2-Py, 4-CF_Three-2-Py, 5-CF_Three-2-Py, 6-CF_Three-2-P
y, 3-Cl-5-CF_Three-2-Py, 3-Me-2-Py, 4-Me-2-Py, 5-Me-2-P
y, 6-Me-2-Py, 3-NO_Two-2-Py, 4-NO_Two-2-Py, 5-NO_Two-2-Py,
6-NO_Two-2-Py Next, 5-chloropyrazole-4-carboxylic acid derivative
The reaction conditions when nitrating (1) are explained in detail.
I will tell.

As the nitrating agent used in the reaction, nitric acid, a combination of nitric acid and sulfuric acid, a combination of nitric acid and acetic anhydride, a combination of nitric acid and trifluoroacetic anhydride, a combination of nitric acid / sulfuric acid and acetic anhydride, acetyl nitrate, sulfuric acid Sodium nitrate, potassium nitrate in sulfuric acid, nitric oxide,
Nitronium tetrafluoroborate, nitronium trifluoromethanesulfonate and the like can be mentioned. These nitrating agents are used alone or in combination.
Among the above nitrating agents, a combination of nitric acid and sulfuric acid, a combination of nitric acid and acetic anhydride, a combination of nitric acid / sulfuric acid and acetic anhydride are preferable, and a combination of nitric acid / sulfuric acid and acetic anhydride is particularly preferable.

The nitrating agent generally includes nitric acid, nitrates, nitric oxide, nitric oxide, nitronium tetrafluoroborate, nitronium trifluoromethanesulfonate, etc., which are sources of nitronium ions (NO ₂ ⁺ ), and is converted to 5-chloropyrazole- 1.0 to 10 based on the 4-carboxylic acid derivative (1)
Good results are obtained when used in a molar amount of 0, preferably 1.0 to 10 times.

The nitrating agent may be charged in its entirety from the beginning of the reaction, or the reaction may be carried out by gradually adding it by dividing, dropping, blowing or the like. Also, in the prepared nitrating agent, 5-chloropyrazole-4-carboxylic acid derivative (1)
A good result can be obtained even when the reaction is carried out by gradually adding, for example, by dividing and dropping. This reaction proceeds sufficiently without solvent when the nitrating agent is a liquid, but a solvent can be used if necessary from the viewpoint of operability. The solvent used is not particularly limited as long as it is inert to the reaction. For example, carbon tetrachloride, 1,2-dichloroethane, 1,1,1
Halogenated hydrocarbons such as 2,2-tetrachloroethane, acetic acid, aliphatic carboxylic acids such as trifluoroacetic acid,
Examples thereof include aliphatic sulfonic acids such as trifluoromethanesulfonic acid, and inorganic mineral acids such as sulfuric acid, nitric acid, and phosphoric acid.

The reaction is generally carried out at a temperature of -50 to 300 ° C, preferably 10 to 100 ° C. When the reaction temperature cannot be increased due to the boiling point of the solvent, the reaction can be carried out under pressure. The reaction time is generally in the range of 0.1 to 100 hours, preferably 1 to 20 hours.

After completion of the reaction, the reaction mixture is poured into water,
A crude product is obtained by filtration, solvent extraction, etc., and if necessary, washing with an aqueous alkali solution, washing with water, etc. is performed, and the 5-chloro-4-nitropyrazole derivative (2) is purified by distillation, recrystallization, chromatographic separation or the like. Can be separated and purified. 5-chloropyrazole which is a starting material for the above reaction
The 4-carboxylic acid derivative (1) can be easily produced by selecting any one of the following reaction formulas 4 to 6.

[0016]

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[Wherein R ² has the same meaning as described above;
R ³ represents a lower alkyl group, and Z represents a halogen atom. Reaction formula 4 shows that the amino group of 3-aminopyrazole-4-carboxylic acid ester (f) is converted to a halogen atom by a Sandmeier reaction, and then the amino group of 5-aminopyrazole-4-carboxylic acid ester (f) is reacted with a chlorinating agent such as N-chlorosuccinimide. Chlorinating the 4-position and hydrolyzing the 4-position alkoxycarbonyl group to give a 5-chloropyrazole-4-carboxylic acid derivative.

[0018]

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[Wherein, R ² has the same meaning as described above (excluding the phenyl group), and R ³ and Z have the same meanings as above. Reaction scheme 5 is to react a 3,5-dichloropyrazole-4-carboxylic acid ester (g) with an alkyl halide (h) in the presence of a base, and then hydrolyze the 4-position alkoxycarbonyl group. To a 5-chloropyrazole-4-carboxylic acid derivative.

[0020]

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[Wherein R ² has the same meaning as described above;
R ⁴ represents a haloalkyl group. In the reaction formula 6, the 3-haloalkyl-5-pyrazolones (i) are converted into 5-chloro-4-formylpyrazoles (j) by a Vilsmeier reaction, and then the formyl group at the 4-position is replaced with potassium permanganate or the like. This shows a method of oxidizing to a 5-chloropyrazole-4-carboxylic acid derivative.

[0022]

[Example 1]

Synthesis of 3,5-dichloro-1-methyl-4-nitropyrazole

[0023]

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Concentrated sulfuric acid 340 is added to a 1000 ml reaction flask.
and fuming nitric acid (specific gravity 1.52) 122 ml.
After the dropwise addition of 70 ml of acetic anhydride at a temperature of not more than 3 ° C., 203 g of 3,5-dichloro-1-methylpyrazole-4-carboxylic acid was added.
(1.04 mol) at 60 to 70 ° C. over 2 hours. After stirring at 70 ° C. for 5 hours, the mixture was cooled, the reaction solution was poured into ice water (1000 ml), and the precipitated solid was collected by filtration.
Washed with water. The obtained solid was dissolved in chloroform (350 ml) and washed with a saturated aqueous solution of sodium carbonate and water.
It was dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was dried to obtain 179 g of the desired product. 84-88 ° C

Reference Example 1 (1) Synthesis of 3,5-dichloro-1-methylpyrazole

[0026]

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113 g (0.58 mol) of 3,5-dichloro-1-methylpyrazole-4-carboxylic acid was added at 300 ° C.
And distilled 51 g of the crude oily substance into chloroform 2
After dissolving in 00 ml, washing with water, distilling off the solvent and distilling off the desired product 44
g was obtained. Boiling point 172-173 ° C

(2) 3,5-dichloro-1-methyl-4
-Synthesis of nitropyrazole

[0029]

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A mixed acid consisting of 20 ml of concentrated sulfuric acid and 6 g of fuming nitric acid was mixed with 8.5 g of 3,5-dichloro-1-methylpyrazole.
A solution of (56 mmol) in acetic anhydride (15 ml) was added dropwise at 20 ° C. or lower. After stirring at room temperature for 48 hours, the mixture was poured into 300 ml of ice water, and the precipitated crystals were collected by filtration, washed with water and dried to obtain the desired product, 5.6.
8 g were obtained. Melting point, 84-88 ° C

Example 2 (1) Synthesis of 5-chloro-3-trifluoromethyl-1-methylpyrazole-4-carboxylic acid

[0032]

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5 g (23.5 mmol) of 5-chloro-3-trifluoromethyl-4-formylpyrazole in 30 ml of water
Was suspended, and a 50 ml aqueous solution of 5.2 g (32.9 mmol) of potassium permanganate was added dropwise at 60 to 70 ° C over 0.5 hours, followed by stirring at 60 ° C for 1 hour. After cooling the reaction mixture, 30 ml of a 10% aqueous solution of potassium hydroxide was added, and the mixture was filtered. The filtrate was acidified with concentrated hydrochloric acid, and the precipitated solid was collected by filtration. The obtained solid was dissolved again in 30 ml of a 10% aqueous solution of potassium hydroxide, and insolubles were removed by filtration. The filtrate was acidified with concentrated hydrochloric acid, and the precipitated solid was collected by filtration, washed with water and dried to obtain 4.3 g of the desired product. 196-197 ° C

(2) Synthesis of 5-chloro-3-trifluoromethyl-1-methyl-4-nitropyrazole

[0035]

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7 ml of concentrated sulfuric acid and fuming nitric acid (specific gravity 1.52)
After adding 2 ml of acetic anhydride dropwise to the mixed acid consisting of 2.5 ml at 10 ° C. or less, 4 g (17.5 mmol) of 5-chloro-3-trifluoromethyl-1-methylpyrazole-4-carboxylic acid.
At 60 to 70 ° C. over 1 hour. 60
After stirring at ~ 70 ° C for 1 hour, the mixture was cooled and the reaction solution was cooled with ice water (7
0 ml), and the precipitated oil was extracted with chloroform. After washing with a saturated aqueous solution of sodium carbonate and water, it was dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was dried to obtain 3.76 g of the desired product. Oil

Reference Example 2 (1) 3,5-Dichloro-1-methylpyrazole-4-
Synthesis of carboxylic acid methyl ester

[0038]

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In a reaction flask purged with nitrogen, solid 3
174.5 g (1.00 mol) of -chloro-1-methylpyrazole-4-carboxylic acid methyl ester was added, and the mixture was heated and melted at 120 ° C with stirring. In it, 180.4 g (1.35 mol) of N-chlorosuccinimide was added to 95
The mixture was introduced at a temperature of １００100 ° C. in one-fifth increments every hour. After the last addition, the mixture was stirred at the same temperature for 2 hours. Then 8
The mixture was cooled to 0 ° C, 1000 ml of carbon tetrachloride was added, and the mixture was cooled to room temperature. The precipitated succinimide was filtered and the succinimide was washed twice with 200 ml of 1,2-dichloroethane. The combined filtrates were washed with a 10% aqueous sodium carbonate solution, washed with water, and then the solvent was distilled off to obtain 210 g of crude crude 3,5-dichloro-1-methylpyrazole-4-carboxylic acid methyl ester. Gas chromatography (OV-
198 g (0.947) by internal standard analysis at 1,120 ° C).
Mol, yield 95%) of 3,5-dichloro-1-methylpyrazole-4-carboxylic acid methyl ester. Melting point 58-59 ° C Boiling point 104-8 ° C / 0.25mm
Hg

(2) Synthesis of 3,5-dichloro-1-methylpyrazole-4-carboxylic acid

[0041]

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3,5-Dichloro- in 100 ml of methanol
20 g (95.7 mmol) of 1-methylpyrazole-4-carboxylic acid methyl ester and 20 ml of a 40% aqueous sodium hydroxide solution were added, and the mixture was refluxed for 2 hours. After distilling off methanol, water (250 ml) was added, and extraction was performed with toluene. The aqueous layer was acidified with concentrated hydrochloric acid, and the precipitated solid was collected by filtration.
After washing with water and drying, 17.5 g of the desired product was obtained. Melting point 222-
224 ° C

Reference Example 3 N-methyl-N- (2-chlorophenyl) -2- (3-
Synthesis of chloro-1-methyl-4-nitropyrazol-5-yloxy) acetamide

[0044]

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3,5-Dichloro-1 synthesized in Example 1
0.63 g (3.2 mm) of -methyl-4-nitropyrazole
ol) and 0.64 g (3.2 mmol) of N-methyl-N- (2-chlorophenyl) glycolic acid amide were dissolved in 5 ml of DMF, and 0.18 g (3.2 mmol) of powdered potassium hydroxide was dissolved.
l) was added. After stirring at room temperature for 0.5 hour, 20 ml of water was added, and the mixture was extracted twice with 20 ml of benzene. After washing with water, the extract was dried over anhydrous sodium sulfate. After evaporating the solvent, a small amount of diisopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried to obtain 0.7 g of the desired product. Melting point 1
52-153 ° C

Reference Example 4 Synthesis of 5-chloro-3-trifluoromethyl-1-methylpyrazole

[0047]

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47.8 g of 3-trifluoromethyl-1-methyl-5-pyrazolone in 250 ml of phosphorus oxychloride
(0.29 mol) and heated under reflux for 24 hours. After distilling off excess phosphorus oxychloride, the mixture was heated to 230 ° C., but the target product was not distilled. Furthermore, after cooling the residue, ice water 1
000 ml, and extracted with chloroform.
The desired product was not obtained at all.

Test Example 1 Test for Weeding Efficacy by Pretreatment of Weed Generation under Flooding Conditions After placing alluvial soil in a 1 / 5000-are Wagner pot, water was added and mixed to obtain a freshwater condition with a depth of 4 cm.
After seeds of Nobie, Konagi, Kikasigusa and Firefly were mixed and sown in the above pot, rice seedlings at the 2.5 leaf stage were transplanted. The pot is placed in a greenhouse at 25 to 30 ° C. to grow the plant, and the N-methyl-N- (2-chlorophenyl) synthesized in Reference Example 3 is brought to a predetermined dose on the water surface on the first day after sowing. ) -2- (3-Chloro-1-methyl-4-nitropyrazol-5-yloxy) acetamide was treated. Three weeks after the treatment, the herbicidal effect on rice and various weeds was visually inspected. 0 is no effect and 5 is a 5-point scale showing complete withering. The results are shown in the table.

The symbols in the tables have the following meanings. A (Nobie), B (Firefly), C (Eel), D (Kikasigusa), a (transplanted rice)

[0051]

[Table 1]

[0052]

According to the method of the present invention, the 5-chloro-4-nitropyrazole derivative (2), which is useful as an intermediate for pharmaceuticals and agrochemicals, is obtained by converting the 5-chloropyrazole-4-carboxylic acid derivative (1) into a nitro compound. The compound can be easily obtained in high yield.

──────────────────────────────────────────────────続 き Continued on front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 231/16 CA (STN) REGISTRY (STN)

Claims (8)

(57) [Claims] (1) Formula (1): [Wherein, R ¹ represents a halogen atom or a C _1-4 haloalkyl group, R ² represents a hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _2-4 alkenyl group, a C _{2- 4} alkynyl group, C _1-2 alkyl group substituted with C _3-6 cycloalkyl group, benzyl group, phenyl group (C _1-4 alkyl group,
It may be substituted by one or more substituents selected from C _1-4 haloalkyl groups, C _1-4 alkoxy groups, C _1-4 haloalkoxy groups, cyano groups, nitro groups and halogen atoms. ) Or a pyridyl group (C _1-4 alkyl group, C _1-4
It may be substituted by one or more substituents selected from haloalkyl groups, C _1-4 alkoxy groups, C _1-4 haloalkoxy groups, cyano groups, nitro groups and halogen atoms. ). 5-chloropyrazole-4 represented by the formula:
Formula (2), characterized by nitrating a carboxylic acid derivative: [In the formula, R ¹ and R ² represent the same meaning as described above. The method for producing a 5-chloro-4-nitropyrazole derivative represented by the formula: 2. R ¹ represents a halogen atom or a C _1-4 haloalkyl group, and R ² represents a C _1-6 alkyl group, a phenyl group (C _1-4 alkyl group, C _1-4 haloalkyl group, C _1- haloalkyl group). _{4 It} may be substituted by one or more substituents selected from an alkoxy group, a cyano group, a nitro group and a halogen atom.) Or a pyridyl group (C _1-4 alkyl group, C _1-4 haloalkyl group, C _{1 May} be substituted by one or more substituents selected from a _-4 alkoxy group, a _C1-4 haloalkoxy group, a cyano group, a nitro group and a halogen atom.)
The method for producing a 5-chloro-4-nitropyrazole derivative according to claim 1, which is represented by the following formula: 3. The method for producing a 5-chloro-4-nitropyrazole derivative according to claim 1, wherein R ¹ represents a halogen atom or a C _1-4 haloalkyl group, and R ² represents a C _1-6 alkyl group. 4. The method according to claim 1, wherein R ¹ represents a chlorine atom or a trifluoromethyl group, and R ² represents a C _1-6 alkyl group.
Of a 5-chloro-4-nitropyrazole derivative of the above. Wherein R ¹ represents a trifluoromethyl group, R ²
Is a C _1-6 alkyl group. The 5-chloro-4-nitropyrazole derivative according to claim 1, wherein 6. The method for producing a 5-chloro-4-nitropyrazole derivative according to claim 1, wherein a combination of nitric acid and sulfuric acid is used as the nitrating agent. 7. The method for producing a 5-chloro-4-nitropyrazole derivative according to claim 1, wherein a combination of nitric acid / sulfuric acid and acetic anhydride is used as the nitrating agent. 8. R ¹  Represents a chlorine atom; ^Two  Is C _1-6  A
5. The 5-chloro-4-nitro of claim 1 represented by an alkyl group.
Pyrazole derivatives.