WO2015003289A1

WO2015003289A1 - 3-fluoroalkyl-1-substituted pyrazole-4-carboxylic acid and the preparation method therefor

Info

Publication number: WO2015003289A1
Application number: PCT/CN2013/000848
Authority: WO
Inventors: 林志刚; 秦东光; 阙利民; 江岳恒; 蔡彤�
Original assignee: 雅本化学股份有限公司
Priority date: 2013-07-12
Filing date: 2013-07-12
Publication date: 2015-01-15

Abstract

Provided are 3-fluoroalkyl-1-substituted pyrazole-4-carboxylic acid and a preparation method therefor. In the method, a fluoroacetic acid derivative, as a starting material, is condensed with an acetamide derivative to form a fluoroacetoacetamide derivative, followed by reacting with an orthoformate to form a 2-alkoxymethylenefluoroacylacetamide derivative, and then reacting with a hydrazine reagent to obtain a 1-substituted-3-fluoroalkylpyrazole-4-amide derivative, which is hydrolysed to obtain 3-fluoroalkyl-1-substituted pyrazole-4-carboxylic acid. The method uses cheap and easily available starting materials, is simple to operate, has low equipment requirements, and is suitable for large-scale industrial production.

Description

3-fluoroalkyl-1-substituted pyrazole-4-carboxylic acid and preparation method thereof

The present invention relates to a 3-fluorodecyl-1-substituted pyrazole-4-carboxylic acid and a process for the preparation thereof. Background art

3-Fluoroindolyl-1-substituted pyrazole-4-carboxylic acid is an important intermediate for some new pesticides, such as books

Isopyrazam (CAS: 881685-58-1), Sedaxane (CAS ι 874967-67-6), Penthiopyrad (CAS: 183675-82-3). Therefore, it is suitable for industrial production.

874967-67-6 881685-58-1 183675-82-3 SUMMARY OF THE INVENTION The technical problem to be solved by the present invention is to provide a 3-fluorodecyl-1-substituted pyrazole-4-carboxylic acid and a process for the preparation thereof.

Specifically, the present invention provides a 3-fluorodecyl-1-substituted pyrazole-4-carboxylic acid having the structure of the following formula VI:

Formula VI Wherein, R ₂ is hydrogen or a fluorine atom;

R ₈ is a lower or lower hydrocarbon of H or C1 to C4.

Preferably, the 3-fluorodecyl-1-substituted pyrazole-4-carboxylic acid is 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid of formula VII and/or 3-Difluoromethyl-1H-pyrazole-4-carboxylic acid shown

Formula VII is covered.

The present invention also provides a process for producing the above 3-fluorodecyl-1-substituted pyrazole-4-carboxylic acid, which

formula

Wherein, R ₂ is hydrogen or a fluorine atom;

R ₃ , R ₄ , R ₅ , and R ₆ are H or a C1 to C4 lower indole hydrocarbon;

2) The fluoroacetoacetamide derivative represented by the above formula is reacted with orthoformate and acetic anhydride to form a 2-decyloxymethylenefluoroacetamide derivative represented by Formula IV.

Wherein, R ₂ is hydrogen or a fluorine atom;

R ₃ , R ₄ , R ₅ , and R ₇ are H or C1 to C4 lower indole hydrocarbons;

Wherein, R ₂ is hydrogen or a fluorine atom;

R ₄ , R ₅ , R ₇ , R ₈ are H or a C1 to C4 lower indole hydrocarbon;

4) A 1-substituted-3-fluorodecylpyrazole-4-amide derivative of the formula V, which is hydrolyzed to give a formula VI 3-fluorodecyl-1-substituted pyrazole-4-carboxylic acid

Formula V Formula VI wherein R ₂ is hydrogen or a fluorine atom;

R ₄ , R ₅ and R ₈ are H or a C1 to C4 lower indole hydrocarbon.

Preferably, in step 1), the fluoroacetic acid derivative of the formula I is ethyl difluoroacetate; the acetamide derivative of the formula II is acetamide; the fluoroacetic acetamide derivative of the formula Ν is Ν, Ν-二Methyl difluoroacetoacetamide.

Preferably, in the step 1), the condensation reaction is carried out in a solventless, organic ether solvent or organic alcohol solvent system, wherein the organic ether solvent is THF or dioxane; and the organic alcohol solvent is methanol or ethanol.

Preferably, in step 2), the 2-nonoxymethylenefluoroacetamide derivative of the formula IV is hydrazine, hydrazine-dimethyl-2-ethoxymethylene difluoroacetoacetyl; The molar ratio of the orthoformate to the fluoroacetoacetamide derivative of the formula III is from 0.8 to 5:1; the molar ratio of the acetic anhydride to the fluoroacetoacetamide derivative of the formula III is from 1 to 6:1.

Preferably, in step 3), the reaction is carried out in a hydrocarbon solvent or an organic ether solvent system, wherein the hydrocarbon solvent is benzene, toluene or xylene; and the organic ether solvent is THF, dioxane or methyl tert. Ether. Preferably, in step 3), the 1-substituted-3-fluorodecylpyrazole-4-amide derivative of the formula V is hydrazine, Ν-dimethyl-3-difluoromethyl-1-methyl Pyrazole-3-amide and/or hydrazine, hydrazine-dimethyl-3-difluoromethyl-1 Η-pyrazole-4-amide.

Preferably, in the step 4), the hydrolysis reaction is carried out by acid hydrolysis or alkali hydrolysis, and the reaction is carried out in an aqueous phase or a water and an organic alcohol solvent system, wherein the acid is hydrochloric acid, hydrobromic acid or sulfuric acid: The base is lithium hydroxide, sodium hydroxide or potassium hydroxide, and the organic alcohol is methanol or ethanol.

Preferably, in step 1), the condensation reaction occurs at -10 ° C to 60 ° C; the reaction in step 2) occurs at 80 ° C to 120 ° C; the reaction of step 3) occurs at -20 ° C to 50 ° °C; The reaction of step 4) occurs at 20 ° C ~ 100 ° C.

The above preparation method is cheap and easy to obtain; the preparation process is simple, the equipment requirements are low, and it is suitable for industrial production.

The above and other objects, features, and advantages of the present invention will become more apparent and understood by the appended claims appended claims detailed description

Example 1

Synthesis of hydrazine, hydrazine-dimethyldifluoroacetoacetamide

In a lOOOO mL reaction flask, 265 g of acetamide was added, cooled to 0 ° C, sodium ethoxide (78.2 g) was added, and 0 to 20 drops of ethyl difluoroacetate (124 g) were added thereto. After reacting for 100 minutes, the temperature was slowly raised to 50 ° C. , reaction for 2 hours, GC monitoring and control of raw materials (difluoroacetic acid ethyl ester) <1%; cooled to 0~10 ° C, slowly added acetic acid (75g) filtered (desalt); solid washed with a small amount of ethanol; combined filtrate minus Pressure concentration (control temperature below 50 ° C) to substantially no fraction residue is product / acetamide mixture ~ 350 g, GC content ~ 43 % (theoretical: 165 g); LC-MS: m / e = 165.

Synthesis of ruthenium, Ν-dimethyl-2-ethoxymethylene difluoroacetoacetamide

In a 2000 mL reaction flask, triethyl orthoformate (267.6 g) and acetic anhydride (276.7 g) were added, and the temperature was slowly raised to ~100 ° C, and hydrazine, Ν-dimethyldifluoroacetoacetamide crude (GC) was added dropwise. Pure product ~ 150g), after the addition, continue to react for 0.5 hours, GC monitoring and control of raw materials (Ν, Ν-dimethyldifluoroacetoacetamide) <0.5%; cooled to 50~60 ° C, concentrated under reduced pressure, residual Roots pump decompression steam Distillation, (removal of low boiling impurities), crude product ~ 220g (>100%); GC purity: ~ 90%; LC-MS: m / e = 221.

Synthesis of hydrazine, hydrazine-dimethyl-3-difluoromethyl-1-methylpyrazole-4-amide

To a 1000 ml reaction flask, add toluene (440 ml), 40% aqueous methylhydrazine solution (110 g), room temperature ~ 20 ° C, add hydrazine, hydrazine-dimethyl-2-ethoxymethylene difluoroacetyl Amide in toluene solution

(220 g / 220 mL), after the addition was completed, the reaction was maintained at 20 to 25 ° C for 1 hour, and the starting material (Ν, Ν-dimethyl-2-ethoxymethylene difluoroacetoacetamide) <0.5% was monitored by HPLC. The aqueous phase was separated, and the aqueous phase was extracted with EtOAc (EtOAc). Ν, Ν-dimethyl-3-difluoromethyl small methylpyrazole-4-amide crude ~ 160g; HPLC purity ~ 90%

(210 nm); LC-MS: m/e = 203.

Synthesis of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid

To a 1000 ml reaction flask, add ethanol (85 ml), hydrazine, hydrazine-dimethyl-3-difluoromethyl-1-methylpyrazole- 4-amide crude ~ 170 g, 20% hydrochloric acid 340 g to warm 60 ° C, After reacting overnight, the starting material (Ν, Ν-dimethyl-3-difluoromethyl-1-methylpyrazole-4-amide) <0.5% was monitored by HPLC. The organic layer was concentrated under reduced pressure. The residue was evaporated to room temperature, and then evaporated to dryness. Purity ~ 98%. LC-MS: m/e = 176.

Example 2

Synthesis of hydrazine, hydrazine-dimethyldifluoroacetoacetamide

In a 100 mL reaction flask, add 100 g of acetamide and 200 g of ethanol; cool to 0 ° C, add sodium ethoxide (78.2 g), and add ethyl difluoroacetate (124 g) dropwise at 0 to 20 ° C. After 100 min, slowly The temperature was raised to 50 ° C, the reaction was carried out for 5 hours, and the GC was used to control the starting material (ethyl difluoroacetate) <2%; cooled to 0 to 10 ° C, slowly added with acetic acid (75 g), filtered (desalted); solid with a small amount of ethanol Washing; combining the filtrates under reduced pressure (control temperature below 50 ° C) to substantially no fraction residue as product / acetamide mixture ~ 200 g, GC content ~ 75 % (theory: 165 g); LC-MS: m/e =165. The solution also contains 5% to 10% of the amide alcoholysis product: ethyl difluoroacetate.

Synthesis of ruthenium, Ν-dimethyl-2-ethoxymethylene difluoroacetoacetamide

In a 2000 mL reaction flask, triethyl orthoformate (267.6 g) and acetic anhydride (276.7 g) were taken. Slowly warm to ~ 100 ° C, add hydrazine, Ν-dimethyldifluoroacetoacetamide crude (GC fold pure ~ 150g _; containing a small amount of ethyl difluoroacetate), add, continue the reaction for 0.5 hours, GC Monitoring and control of raw materials (Ν, Ν-dimethyldifluoroacetoacetamide) <0.5%; cooled to 50~60 ° C, concentrated under reduced pressure, residual Roots pump distillation under reduced pressure, (removal of low boiling impurities), Crude product ~220g (>100%); GC purity: ~85%; LC-MS: m/e=221. Containing ethyl 2-ethoxymethylene-difluoroacetoacetate.

To a 1000 ml reaction flask, add methyl tert-butyl ether MTBE (440 ml), 40% aqueous methyl hydrazine solution (110 g), room temperature ~ 20 ° C, add hydrazine, hydrazine-dimethyl-2-ethoxyl A solution of methyl difluoroacetoacetamide (220 g / 220 mL), after completion of the addition, maintaining a reaction at 20 to 25 ° C for 1 hour, HPLC monitoring of the starting material (Ν, Ν-dimethyl-2-ethoxymethylene II Fluoroacetoacetamide <0.5%. The aqueous phase was separated, and the aqueous phase was extracted with EtOAc EtOAc (EtOAc). Ν, Ν-dimethyl-3-difluoromethyl small methylpyrazole-4-amide crude ~ 170 g; HPLC purity ~ 90% (210nm); LC-MS: m / e = 203.

Synthesis of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid

To a 1000 ml reaction flask, add ethanol (85 ml), hydrazine, hydrazine-dimethyl-3-difluoromethyl-1-methylpyrazole- 4-amide crude ~ 170 g, 20% liquid base 340g warming 60 ° C After reacting overnight, the starting material (Ν, Ν-dimethyl-3-difluoromethyl-1-methylpyrazole-4-amide) <0.5% was monitored by HPLC. The organic layer was concentrated under reduced pressure. The residue was evaporated and evaporated to ethyl ether. Purity ~ 98%. LC-MS: m/e = 176.

Example 3

Synthesis of hydrazine, hydrazine-dimethyldifluoroacetoacetamide

In a 1000 mL reaction flask, 100 g of acetamide and 200 g of anhydrous tetrahydrofuran were added; after cooling to 0 ° C, sodium ethoxide (78.2 g) was added, and ethyl difluoroacetate (124 g) was added dropwise at 0 to 20 ° C, after reacting for 100 min. Slowly raise the temperature to 50 ° C, react for 2 hours, control the raw material (ethyl difluoroacetate) <2% by GC, cool to 0~10 ° C, slowly add acetic acid (75 g), filter (desalt); A small amount of tetrahydrofuran was washed; the combined filtrate was concentrated under reduced pressure (control temperature below 50 ° C) to a substantially fraction-free residue as product / acetamide mixture ~ 190 g, GC purity ~ 80% (theoretical: 165 g); LC-MS: m/e=165.

Synthesis of ruthenium, Ν-dimethyl-2-ethoxymethylene difluoroacetoacetamide

In a 2000 mL reaction flask, triethyl orthoformate (267.6 g) and acetic anhydride (276.7 g) were added, and the temperature was slowly raised to ~100 °C, and hydrazine, hydrazine-dimethyldifluoroacetoacetamide crude (GC) was added dropwise. Pure product ~ 150g), after the addition, continue to react for 0.5 hours, GC monitoring and control of raw materials (Ν, Ν-dimethyldifluoroacetoacetamide) <0.5%; cooled to 50~60 ° C, concentrated under reduced pressure, residual The Roots pump was distilled under reduced pressure (to remove low boiling impurities) to give a crude product ~220 g (>100%); GC purity: ~ 90%; LC-MS: m/e = 221.

To a 1000 ml reaction flask, add toluene (440 ml), 40% aqueous methylhydrazine solution (110 g), room temperature ~ 20 ° C, add hydrazine, hydrazine-dimethyl-2-ethoxymethylene difluoroacetyl Toluene solution of amide (220g/220mL; containing 2-ethoxymethylene-difluoroacetoacetate), after completion, maintain reaction at 20~25°C for 1 hour, HPLC monitoring of raw materials (Ν,Ν-dimethyl Base-2-ethoxymethylene difluoroacetoacetamide <0.5%. The aqueous phase was separated, and the aqueous phase was extracted with a mixture of toluene, 220 ml, and the organic phase was combined, washed with brine and concentrated to dryness. Ν, Ν-dimethyl-3-difluoromethyl-1-methylpyrazole-4-amide crude ~ 170 g _; HPLC purity ~ 85 % (210 nm); LC-MS: m / e = 203. Contains a small amount of ethyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate.

Synthesis of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid

Example 4

Synthesis of hydrazine, hydrazine-dimethyldifluoroacetoacetamide

In a 1000 mL reaction flask, 100 g of acetamide and 200 g of anhydrous tetrahydrofuran were added; after cooling to 0 ° C, sodium ethoxide (78.2 g) was added, and ethyl difluoroacetate (124 g) was added dropwise at 0 to 20 ° C for 100 min. After that, the temperature was slowly raised to 50 ° C, and the reaction was carried out for 2 hours. The GC monitored the starting material (ethyl difluoroacetate) <2%; cooled to 0 to 10 ° C, slowly added with acetic acid (75 g), filtered (desalted); Washing with a small amount of tetrahydrofuran; concentrating the filtrate under reduced pressure (control temperature below 50 ° C) to substantially no fraction residue as product / acetamide mixture ~ 190 g, GC purity ~ 80% (theoretical: 165 g); LC-MS: m/e=165.

Synthesis of ruthenium, Ν-dimethyl-2-ethoxymethylene difluoroacetoacetamide

Synthesis of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid

Example 5 Synthesis of hydrazine, hydrazine-dimethyldifluoroacetoacetamide

Synthesis of ruthenium, Ν-dimethyl-2-ethoxymethylene difluoroacetoacetamide

In a 2000 mL reaction flask, triethyl orthoformate (267.6 g) and acetic anhydride (276.7 g) were added, and the temperature was slowly raised to ~100 ° C, and hydrazine, Ν-dimethyldifluoroacetoacetamide crude (GC) was added dropwise. Pure product ~ 150g), after the addition, continue to react for 0.5 hours, GC monitoring and control of raw materials (Ν, Ν-dimethyldifluoroacetoacetamide) <0.5%; cooled to 50~60 ° C, concentrated under reduced pressure, residual The Roots pump was distilled under reduced pressure (to remove low boiling impurities) to give a crude product ~220 g (>100%); GC purity: ~ 90%; LC-MS: m/e = 221.

Synthesis of hydrazine, hydrazine-dimethyl-3-difluoromethyl-1H-pyrazole-4-amide

To a 1000 ml reaction flask, add toluene (440 ml), 40% aqueous hydrazine hydrate solution (100 g), room temperature ~ 20 ° C, add hydrazine, hydrazine-dimethyl-2-ethoxymethylene difluoroacetamide Toluene solution

(220 g / 220 mL), after the addition was completed, the reaction was maintained at 20 to 25 ° C for 1 hour, and the starting material (Ν, Ν-dimethyl-2-ethoxymethylene difluoroacetoacetamide) <0.5% was monitored by HPLC. The aqueous phase was separated, and the aqueous phase was extracted with EtOAc (EtOAc). Ν, Ν-dimethyl-3-difluoromethyl-1Η-pyrazole-4-amide crude ~ 160g; HPLC purity ~ 95 %

(210 nm); LC-MS: m/e = 189.

Synthesis of 3-difluoromethyl-1H-pyrazole-4-carboxylic acid

To a 1000 ml reaction flask, add ethanol (85 ml), hydrazine, hydrazine-dimethyl-3-difluoromethyl-1H-pyrazole- 4-amide crude ~ 160 g, 20% hydrochloric acid 340 g, warm at 60 ° C, overnight reaction The starting material (Ν, Ν-dimethyl-3-difluoromethyl-1H-pyrazole-4-amide) <0.5% was monitored by HPLC. Concentration under reduced pressure, evaporation of ethanol, the residue was cooled to room temperature, and then solids were separated, filtered, washed with water and dried Purity ~ 98%. LC-MS: m/e = 162. Example 6

Synthesis of hydrazine, hydrazine-dimethyldifluoroacetoacetamide

Synthesis of ruthenium, Ν-dimethyl-2-ethoxymethylene difluoroacetoacetamide

In a 2000 mL reaction flask, triethyl orthoformate (267.6 g) and acetic anhydride (276.7 g) were added, and the temperature was slowly raised to ~100 °C, and hydrazine, hydrazine-dimethyldifluoroacetoacetamide crude (GC) was added dropwise. Pure product ~ 150g _; containing a small amount of ethyl difluoroacetate), after the addition, continue the reaction for 0.5 hours, GC monitoring and control of raw materials (Ν, Ν-dimethyldifluoroacetoacetamide) <0.5%; cooled to 50~ At 60 ° C, concentrated under reduced pressure, and the residue Roots pump was distilled under reduced pressure (removing low boiling impurities) to obtain crude product ~220 g (>100%); GC purity: ~85%; LC-MS: m/e= 221. Containing ethyl 2-ethoxymethylene-difluoroacetoacetate.

Synthesis of hydrazine, hydrazine-dimethyl-3-difluoromethyl-1H-pyrazole-4-amide

(210 nm); LC-MS: m/e = 189.

Synthesis of 3-difluoromethyl-1H-pyrazole-4-carboxylic acid Ft

Into a 1000 ml reaction flask, add ethanol (85 ml), Ν, Ν-dimethyl-3-difluoromethyl-1H-pyrazole-4-amide crude ~ 170 g, 20% liquid base 340g temperature 60 ° C, reaction Overnight, the starting material (Ν, Ν-dimethyl-3-difluoromethyl-1H-pyrazole-4-amide) <0.5% was monitored by HPLC. The organic layer was concentrated under reduced pressure. The residue was evaporated and evaporated to ethyl ether. Purity ~ 25 %. LC-MS: m/e = 162.

Example 7

Synthesis of hydrazine, hydrazine-dimethyldifluoroacetoacetamide

In a 1000 mL reaction flask, 100 g of acetamide and 200 g of anhydrous tetrahydrofuran were added; after cooling to 0 ° C, sodium ethoxide (78.2 g) was added, and 2:20 ° C was added dropwise: ethyl fluoroacetate (124 g) was reacted. After lOOmin, slowly heat up to 50 ° C, reaction for 2 hours, GC monitoring and control of raw materials (difluoroacetate) <2%; cooled to 0~10 ° C, slowly added acetic acid (75g) filtered (desalt); The solid was washed with a small amount of tetrahydrofuran; the combined filtrate was concentrated under reduced pressure (control temperature below 50 ° C) to a substantially fraction free residue product / acetamide mixture ~ 190 g, GC purity ~ 80% (theoretical: 165 g); LC-MS : m/e=165.

Synthesis of ruthenium, Ν-dimethyl-2-ethoxymethylene difluoroacetoacetamide

Synthesis of hydrazine, hydrazine-dimethyl-3-difluoromethyl-1H-pyrazole-4-amide

To a 1000 ml reaction flask, add toluene (440 ml), 40% aqueous hydrazine hydrate solution (100 g), room temperature ~ 20 ° C, add hydrazine, hydrazine-dimethyl-2-ethoxymethylene difluoroacetamide Toluene solution (220g / 220mL), after the addition, maintain the reaction at 20~25 ° C for 1 hour, HPLC monitoring of the starting material (Ν, Ν-dimethyl-2-ethoxymethylene difluoroacetoacetamide) <0.5 %. The aqueous phase was separated, and the aqueous phase was extracted with EtOAc (EtOAc). Success, Ν- Crude dimethyl-3-difluoromethyl-1H-pyrazole-4-amide ~ 160 g; HPLC purity ~ 95% (210nm); LC-MS: m/e = 189.

Synthesis of 3-difluoromethyl-1H-pyrazole-4-carboxylic acid

To a 1000 ml reaction flask, add ethanol (85 ml), hydrazine, hydrazine-dimethyl-3-difluoromethyl-1H-pyrazole- 4-amide crude ~ 160 g, 20% hydrochloric acid 340 g, warm at 60 ° C, overnight reaction The starting material (Ν, Ν-dimethyl-3-difluoromethyl-1H-pyrazole-4-amide) <0.5% was monitored by HPLC. The organic layer was concentrated under reduced pressure. The residue was evaporated to room temperature, and then evaporated to dryness. Purity ~ 98%. LC-MS: m/e = 162.

Example 8

Synthesis of hydrazine, hydrazine-dimethyldifluoroacetoacetamide

In a 1000 mL reaction flask, 100 g of acetamide and 200 g of anhydrous tetrahydrofuran were added; after cooling to 0 ° C, sodium ethoxide (78.2 g) was added, and ethyl difluoroacetate (124 g) was added dropwise at 0 to 20 ° C, after reacting for 100 min. Slowly raise the temperature to 50 ° C, react for 2 hours, control the raw material (ethyl difluoroacetate) <2% by GC, cool to 0~10 ° C, slowly add acetic acid (75 g), filter (desalt); A small amount of tetrahydrofuran was washed; the combined filtrate was concentrated under reduced pressure (control temperature below 50 ° C) to a substantially fraction-free residue as product / acetamide mixture ~ 190 g, GC purity ~ 80% (theoretical: 165 g); LC-MS: m /e=165.

Synthesis of ruthenium, Ν-dimethyl-2-ethoxymethylene difluoroacetoacetamide

Synthesis of hydrazine, hydrazine-dimethyl-3-difluoromethyl-1H-pyrazole-4-amide

To a 1000 ml reaction flask, add toluene (440 ml), 40% aqueous hydrazine hydrate solution (100 g), room At a temperature of ~ 20 ° C, add hydrazine, hydrazine-dimethyl-2-ethoxymethylene difluoro acetoacetamide in toluene solution (220g / 220mL), add, maintain 20 ~ 25 ° C reaction for 1 hour The material was monitored by HPLC (Ν, Ν-dimethyl-2-ethoxymethylene difluoroacetoacetamide) <0.5%. The aqueous phase was separated, and the aqueous phase was extracted with EtOAc (EtOAc). Ν, Ν-dimethyl-3-difluoromethyl-1 Η-pyrazole-4-amide crude ~ 160 g; HPLC purity ~ 95% (210nm); LC-MS: m / e = 189.

Synthesis of 3-difluoromethyl-1H-pyrazole-4-carboxylic acid

Into a 1000 ml reaction flask, add ethanol (85 ml), hydrazine, hydrazine-dimethyl-3-difluoromethyl-1H-pyrazole- 4-amide crude ~ 170 g, 20% liquid base 340 g temperature 60 ° C, reaction Overnight, the starting material (Ν, Ν-dimethyl-3-difluoromethyl-1H-pyrazole-4-amide) <0.5% was monitored by HPLC. The organic layer was concentrated under reduced pressure. The residue was evaporated and evaporated to ethyl ether. Purity ~ 25 %. LC-MS: m/e = 162.

Although the present invention has been disclosed in the above preferred embodiments, it is not intended to limit the invention, and those skilled in the art can make some modifications and improvements without departing from the spirit and scope of the invention. Therefore, the scope of the invention is defined by the claims.

Claims

Claim

A 3-fluorodecyl-1-substituted pyrazole-4-carboxylic acid having the following formula VI

Wherein, R ₂ is hydrogen or a fluorine atom; and R ₈ is a lower alkylene group of H or C1 to C4.

The 3-fluorodecyl-1-substituted pyrazole-4-carboxylic acid according to claim 1, wherein the 3-fluorodecyl-1-substituted pyrazole-4-carboxylic acid 3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid of the formula VII and/or 3-difluoromethyl-1H-pyrazole-4-carboxylic acid of the formula

VD type.

3. A process for preparing 3-fluorodecyl-1-oxazol-4-carboxylic acid according to claim 1

Wherein, R ₂ is hydrogen or a fluorine atom;

R ₃ , R ₄ , R ₅ , and R ₆ are H or a C1 to C4 lower indole hydrocarbon; 2) The action of the fluoroacetoacetamide derivative represented by the formula m with orthoformate and acetic anhydride forms a 2-decyloxymethylenefluoroacetamide derivative represented by the formula IV

Wherein R ₂ is hydrogen or a fluorine atom;

R ₃ , R ₄ , R ₅ , and R ₇ are H or C1 to C4 lower indole hydrocarbons;

3) The 2-decyloxymethylenefluoroacetamide derivative represented by the formula IV is cyclized with a hydrazine reagent to obtain a 1-substituted-3-fluorodecylpyrazole-4- represented by the formula V. Amide derivative

Wherein, R ₂ is hydrogen or a fluorine atom;

R ₄ , R ₅ , R ₇ , R ₈ are H or a C1 to C4 lower indole hydrocarbon;

4) The 1-substituted-3-fluorodecylpyrazole-4-amide derivative represented by the formula V is hydrolyzed to give 3-fluorodecyl-1-pyrazole-4- represented by the formula VI Carbohydrate

Wherein, R ₂ is hydrogen or a fluorine atom;

R ₄ , R ₅ , or 11 or C1 to C4 lower indole hydrocarbons.

The method according to claim 3, wherein in step 1), the fluoroacetic acid derivative of the formula I is ethyl difluoroacetate; the acetamide derivative of the formula is acetamide; the fluorine of the formula III The acetoacetamide derivative is hydrazine, hydrazine-dimethyldifluoroacetoacetamide.

5. The method according to claim 3, wherein in step 1), the condensation reaction In a solvent-free, organic ether solvent or organic alcohol solvent system, wherein the ether solvent is

THF or dioxane; the organic alcohol solvent is methanol or ethanol.

The method according to claim 3, wherein in the step 2), the 2-nonoxymethylenefluoroacetamide derivative of the formula IV is ruthenium, osmium-dimethyl-2 - ethoxymethylene difluoroacetoacetyl; molar ratio of orthoformate to fluoroacetoacetamide derivative of formula 0.8 0.8 - 5: 1; acetic anhydride and fluoroacetoacetamide derivative of formula III The molar ratio is 1~6: 1.

The method according to claim 3, wherein in the step 3), the reaction is carried out in a hydrocarbon solvent or an organic ether solvent system, wherein the hydrocarbon solvent is benzene, toluene or xylene; and the organic ether solvent It is THF, dioxane or methyl tert-butyl ether.

The method according to claim 3, wherein in the step 3), the 1-substituted-3-fluorodecylpyrazole-4-amide derivative of the formula V is ruthenium, osmium-dimethyl Alkyl-3-difluoromethyl-1-methylpyrazole- 4-amide and/or hydrazine, hydrazine-dimethyl-3-difluoromethyl-1 Η-pyrazole-4-amide.

The method according to claim 3, wherein in the step 4), the hydrolysis reaction is carried out by acid hydrolysis or alkali hydrolysis, and the reaction is carried out in an aqueous phase or a water and an organic alcohol solvent system, wherein The acid is hydrochloric acid, hydrobromic acid or sulfuric acid: the base is lithium hydroxide, sodium hydroxide or potassium hydroxide, and the organic alcohol is methanol or ethanol.

10. The method according to claim 3, wherein in the step 1), the condensation reaction occurs at -10 ° C to 60 ° C; the reaction in the step 2) occurs at 80 ° C to 120 ° C; The reaction in 3) occurs at -20 ° C to 50 ° C; the reaction in step 4) occurs at 20 ° C to 100 ° C.