CN103360313A - 3-fluoroalkyl-1-substituted-pyrazolyl-4-carboxylic acid and preparation method thereof - Google Patents
3-fluoroalkyl-1-substituted-pyrazolyl-4-carboxylic acid and preparation method thereof Download PDFInfo
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Abstract
The invention provides 3-fluoroalkyl-1-substituted-pyrazolyl-4-carboxylic acid and a preparation method thereof. The method comprises the following steps: condensing cheap and accessible fluoroacetic acid derivatives used as the initial raw material with acetamide derivatives to form fluoroacetoacetamide derivatives, reacting with and acetic anhydride to form 2-alkoxymethylenefluoroacylacetamide derivatives, reacting with a hydrazine reagent to obtain 1-substituted-3-fluoroalkylpyrazolyl-4-amide derivatives, and hydrolyzing to obtain the 3-fluoroalkyl-1-substituted-pyrazolyl-4-carboxylic acid. The preparation method has the advantages of cheap and accessible raw materials, simple operation in the preparation process, low facility request, and is suitable for industrialized mass production.
Description
Technical field
The present invention relates to a kind of 3-fluoro-alkyl-1-substituted pyrazolecarboxylic-4-carboxylic acid and preparation method thereof.
Background technology
3-fluoro-alkyl-1-substituted pyrazolecarboxylic-4-carboxylic acid is the important intermediate of some novel agrochemicals, such as lsopyrazam (CAS:881685-58-1), and Sedaxane (CAS:874967-67-6), Penthiopyrad (CAS:183675-82-3).Therefore the preparation method who studies its suitable suitability for industrialized production is significant
Summary of the invention
Technical problem to be solved by this invention provides a kind of 3-fluoro-alkyl-1-substituted pyrazolecarboxylic-4-carboxylic acid and preparation method thereof.
Particularly, the invention provides a kind of 3-fluoro-alkyl-1-substituted pyrazolecarboxylic-4-carboxylic acid, have following formula VI structure:
Wherein, R
1, R
2Hydrogen, fluorine atom;
R
8It is the lower paraffin hydrocarbons of H or Cl～C4.
Preferably, described 3-fluoro-alkyl-1-substituted pyrazolecarboxylic-4-carboxylic acid is the 3-difluoromethyl shown in the 3-difluoromethyl shown in the formula VII-1-methylpyrazole-4-formic acid and/or the formula VIII-1H-pyrazoles-4-formic acid
The present invention also provides the preparation method of above-mentioned 3-fluoro-alkyl-1-substituted pyrazolecarboxylic-4-carboxylic acid, and it mainly comprises step:
1) take the acetamide derivative of the fluoro acetogenin shown in the formula I and formula II as raw material, condensation forms the fluoro acetoacetyl sulfonamide derivatives shown in the formula III under the effect of sodium alkoxide
Wherein, R
1, R
2Hydrogen, fluorine atom;
R
3, R
4, R
5, R
6It is the lower paraffin hydrocarbons of H or Cl～C4;
2) effect of the fluoro acetoacetyl sulfonamide derivatives shown in the described formula III and ortho-formiate, aceticanhydride forms the 2-alkoxyl group methylene radical fluoro acyl group acetamide derivative shown in the formula IV
Wherein, R
1, R
2Hydrogen, fluorine atom;
R
3, R
4, R
5, R
7It is the lower paraffin hydrocarbons of H or Cl～C4;
3) the 2-alkoxyl group methylene radical fluoro acyl group acetamide derivative shown in the described formula IV and the cyclization of hydrazine class reagent obtain the 1-replacement-3-fluoroalkyl pyrazole shown in the formula V-4-amide derivatives
Wherein, R
1, R
2Hydrogen, fluorine atom;
R
4, R
5, R
7, R
8It is the lower paraffin hydrocarbons of H or Cl～C4;
4) the 1-replacement-3-fluoroalkyl pyrazole shown in the described formula V-4-amide derivatives obtains the 3-fluoro-alkyl shown in the formula VI-1-substituted pyrazolecarboxylic-4-carboxylic acid through hydrolysis
Wherein, R
1, R
2Hydrogen, fluorine atom;
R
4, R
5, R
8It is the lower paraffin hydrocarbons of H or C1～C4.
Preferably, step 1) in, the fluoro acetogenin of formula I is ethyl difluoro; The acetamide derivative of formula II is ethanamide; The fluoro acetoacetyl sulfonamide derivatives of formula III is N, N-dimethyl difluoro aceto-acetamide.
Preferably, step 1) in, condensation reaction is carried out in solvent-free, organic ether kind solvent or organic alcohols solvent system, and wherein the machine ether solvent is THF or dioxane; The organic alcohols solvent is methyl alcohol or ethanol.
Preferably, step 2) in, the 2-alkoxyl group methylene radical fluoro acyl group acetamide derivative of described formula IV is N, N-dimethyl-2-oxyethyl group methylene radical difluoro acetoacetyl; The mol ratio of the fluoro acetoacetyl sulfonamide derivatives of ortho-formiate and formula III is 0.8～5:1; The mol ratio of the fluoro acetoacetyl sulfonamide derivatives of aceticanhydride and formula III is 1～6:1.
Preferably, step 3) in, reaction is carried out in varsol or organic ether kind solvent system, and wherein varsol is benzene, toluene or dimethylbenzene; The organic ether kind solvent is THF, dioxane or methyl tertiary butyl ether.
Preferably, step 3) in, the 1-replacement-3-fluoroalkyl pyrazole of described formula V-the 4-amide derivatives is N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides and/or N, N-dimethyl-3-difluoromethyl-lH-pyrazoles-4-acid amides.
Preferably, step 4) in, described hydrolysis reaction is with acid hydrolysis or basic hydrolysis, reaction is carried out in water or water and organic alcohols solvent system, wherein, described acid is hydrochloric acid, Hydrogen bromide or sulfuric acid: described alkali is lithium hydroxide, sodium hydroxide or potassium hydroxide, and described Organic Alcohol is methyl alcohol or ethanol.
Preferably, step 1) in, condensation reaction occurs in-10 ° of C～60 ° C; Step 2) reaction in occurs in 80 ° of C～l20 ° of C; Step 3) reaction occurs in-20 ° of C～50 ° C; Step 4) reaction occurs in 20 ° of C～l00 ° of C.
Above-mentioned preparation method's starting material are cheap and easy to get; Preparation process is simple to operate, and equipment requirements is low, is fit to industrialized production.
State with other objects, features and advantages and can become apparent on the present invention for allowing, preferred embodiment cited below particularly is described in detail below.
Embodiment
Embodiment 1
N, N-dimethyl difluoro aceto-acetamide synthetic
In the 1000mL reaction flask, add ethanamide 265g, be cooled to 0 ° of C, add sodium ethylate (78.2g), control 0～20 ° of C and drip ethyl difluoro (124g), behind the reaction 100min, slowly be warming up to 50 ° of C, reacted GC Monitoring and Controlling raw material (ethyl difluoro)＜1% 2 hours; Be cooled to 0～10 ° of C, slowly drip acetic acid (75g) and filter (desalination); Solid is with a small amount of washing with alcohol; Merging filtrate concentrating under reduced pressure (the control temperature is lower than 50 ° of C) is product/ethanamide mixed solution～350g without the cut resistates substantially extremely, GC content～43% (theory: 165g); LC-MS:m/e=165.
N, N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide synthetic
In the 2000mL reaction flask, suction triethyl orthoformate (267.6g), aceticanhydride (276.7g), slowly be warming up to～100 ° of C, drip N, and N-dimethyl difluoro aceto-acetamide crude product (the pure product of GC～150g), add, continue reaction 0.5 hour, GC Monitoring and Controlling raw material (N, N-dimethyl difluoro aceto-acetamide)＜0.5%; Be cooled to 50～60 ° of C, concentrating under reduced pressure, the underpressure distillation of resistates lobe pump, (removing the low impurity that boils) gets thick product～220g (＞100%); GC purity :～90%; LC-MS:m/e=221.
N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides synthetic
In the 1000ml reaction flask, add toluene (440ml), the 40% methyl hydrazine aqueous solution (110g), room temperature～20 ° C drips N, the toluene solution (220g/220mL) of N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide, add, keep 20～25 ° of C reactions 1 hour, HPLC monitors raw material (N, N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide)＜0.5%.Divide the phase of anhydrating, water merges organic phase after extracting 1 time with toluene 220ml, and the salt solution washing is evaporated to dried.Get N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides crude product～160g; HPLC purity～90% (2l0nm); LC-MS:m/e=203.
Synthesizing of 3-difluoromethyl-1-methylpyrazole-4-formic acid
In the 1000ml reaction flask, add ethanol (85ml), N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides crude product～170g, 20% hydrochloric acid 340g, the 60 ° of C that heat up, reaction is spent the night, and HPLC monitors raw material (N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides)＜0.5%.Concentrating under reduced pressure boils off ethanol, and residual solution is cooled to room temperature, separates out solid, filters washing, the dry product～120g that gets.Purity～98%.LC-MS:m/e=176。
Embodiment 2
N, N-dimethyl difluoro aceto-acetamide synthetic
In the 1000mL reaction flask, add ethanamide 100g, ethanol 200g: be cooled to 0 ° of C, add sodium ethylate (78.2g), control 0～20 ° of C and drip ethyl difluoro (124g), behind the reaction 100min, slowly be warming up to 50 ° of C, reacted GC Monitoring and Controlling raw material (ethyl difluoro)＜2% 5 hours; Be cooled to 0～10 ° of C, slowly drip acetic acid (75g) and filter (desalination); Solid is with a small amount of washing with alcohol; Merging filtrate concentrating under reduced pressure (the control temperature is lower than 50 ° of C) is product/ethanamide mixed solution～200g without the cut resistates substantially extremely, GC content～75% (theory: 165g); LC-MS:m/e=165.Also contain 5%～10% acid amides alcoholysis product in the solution: the difluoro methyl aceto acetate.
N, N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide synthetic
In the 2000mL reaction flask, suction triethyl orthoformate (267.6g), aceticanhydride (276.7g) slowly is warming up to～100 ° of C, drips N, the N-dimethyl difluoro aceto-acetamide crude product (pure product～150g of GC; Contain a small amount of difluoro methyl aceto acetate), add, continue reaction 0.5 hour, GC Monitoring and Controlling raw material (N, N-dimethyl difluoro aceto-acetamide)＜0.5%; Be cooled to 50～60 ° of C, concentrating under reduced pressure, the underpressure distillation of resistates lobe pump, (removing the low impurity that boils) gets thick product～220g (＞100%); GC purity :～85%; LC-MS:m/e=221.Contain 2-oxyethyl group methylene radical-difluoro etheric acid acetyl.
N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides synthetic
In the 1000ml reaction flask, add methyl tertiary butyl ether MTBE (440ml), the 40% methyl hydrazine aqueous solution (110g), room temperature～20 ° C drips N, the MTBE solution (220g/220mL) of N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide, add, keep 20～25 ° of C reactions 1 hour, HPLC monitors raw material (N, N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide)＜0.5%.Divide the phase of anhydrating, water merges organic phase after extracting 1 time with MTBE220ml, and the salt solution washing is evaporated to dried.Get N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides crude product～170g; HPLC purity～90% (2l0nm); LC-MS:m/e=203.
Synthesizing of 3-difluoromethyl-1-methylpyrazole-4-formic acid
In the 1000ml reaction flask, add ethanol (85ml), N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides crude product～170g, 20% liquid caustic soda 340g, the 60 ° of C that heat up, reaction is spent the night, and HPLC monitors raw material (N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides)＜0.5%.Concentrating under reduced pressure boils off ethanol, and residual solution adds 31% hcl acidifying to pH～l, is cooled to room temperature, separates out solid, filters washing, the dry product～120g that gets.Purity～98%.LC-MS:m/e=176。
Embodiment 3
N, N-dimethyl difluoro aceto-acetamide synthetic
In the 1000mL reaction flask, add ethanamide 100g, anhydrous tetrahydro furan 200g; Be cooled to 0 ° of C, add sodium ethylate (78.2g), control 0～20 ° of C and drip ethyl difluoro (124g), behind the reaction 100min, slowly be warming up to 50 ° of C, reacted GC Monitoring and Controlling raw material (ethyl difluoro)＜2% 2 hours; Be cooled to 0～10 ° of C, slowly drip acetic acid (75g) and filter (desalination); Solid washs with a small amount of tetrahydrofuran (THF); Merging filtrate concentrating under reduced pressure (the control temperature is lower than 50 ° of C) is product/ethanamide mixed solution～190g without the cut resistates substantially extremely, GC purity～80% (theory: 165g); LC-MS:m/e=165.
N, N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide synthetic
In the 2000mL reaction flask, suction triethyl orthoformate (267.6g), aceticanhydride (276.7g), slowly be warming up to～100 ° of C, drip N, and N-dimethyl difluoro aceto-acetamide crude product (the pure product of GC～150g), add, continue reaction 0.5 hour, GC Monitoring and Controlling raw material (N, N-dimethyl difluoro aceto-acetamide)＜0.5%; Be cooled to 50～60 ° of C, concentrating under reduced pressure, the underpressure distillation of resistates lobe pump, (removing the low impurity that boils) gets thick product～220g (＞100%); GC purity :～90%; LC-MS:m/e=221.
N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides synthetic
In the 1000ml reaction flask, add toluene (440ml), the 40% methyl hydrazine aqueous solution (110g), room temperature～20 ° C drips N, the toluene solution (220g/220mL of N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide; Contain 2-oxyethyl group methylene radical-difluoro methyl aceto acetate), add, keep 20～25 ° of C reactions 1 hour, HPLC monitors raw material (N, N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide)＜0.5%.Divide the phase of anhydrating, water merges organic phase after extracting 1 time with toluene 220ml, and the salt solution washing is evaporated to dried.Get N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides crude product～170g; HPLC purity～85% (210nm); LC-MS:m/e=203.Contain a small amount of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid, ethyl ester.
Synthesizing of 3-difluoromethyl-1-methylpyrazole-4-formic acid
In the 1000ml reaction flask, add ethanol (85ml), N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides crude product～170g, 20% liquid caustic soda 340g, the 60 ° of C that heat up, reaction is spent the night, and HPLC monitors raw material (N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides)＜0.5%.Concentrating under reduced pressure boils off ethanol, and residual solution adds 31% hcl acidifying to pH～l, is cooled to room temperature, separates out solid, filters washing, the dry product～120g that gets.Purity～98%.LC-MS:m/e=176。
Embodiment 4
N, N-dimethyl difluoro aceto-acetamide synthetic
In the 1000mL reaction flask, add ethanamide 100g, anhydrous tetrahydro furan 200g; Be cooled to 0 ° of C, add sodium ethylate (78.2g), control 0～20 ° of C and drip ethyl difluoro (124g), behind the reaction 100min, slowly be warming up to 50 ° of C, reacted GC Monitoring and Controlling raw material (ethyl difluoro)＜2% 2 hours; Be cooled to 0～10 ° of C, slowly drip acetic acid (75g) and filter (desalination); Solid washs with a small amount of tetrahydrofuran (THF); Merging filtrate concentrating under reduced pressure (the control temperature is lower than 50 ° of C) is product/ethanamide mixed solution～190g without the cut resistates substantially extremely, GC purity～80% (theory: 165g); LC-MS:m/e=165.
N, N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide synthetic
In the 2000mL reaction flask, suction triethyl orthoformate (267.6g), aceticanhydride (276.7g), slowly be warming up to～100 ° of C, drip N, and N-dimethyl difluoro aceto-acetamide crude product (the pure product of GC～150g), add, continue reaction 0.5 hour, GC Monitoring and Controlling raw material (N, N-dimethyl difluoro aceto-acetamide)＜0.5%; Be cooled to 50～60 ° of C, concentrating under reduced pressure, the underpressure distillation of resistates lobe pump, (removing the low impurity that boils) gets thick product～220g (＞100%); GC purity :～90%; LC-MS:m/e=221.
N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides synthetic
In the 1000ml reaction flask, add toluene (440ml), the 40% methyl hydrazine aqueous solution (110g), room temperature～20 ° C drips N, the toluene solution (220g/220mL of N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide; Contain 2-oxyethyl group methylene radical-difluoro methyl aceto acetate), add, keep 20～25 ° of C reactions 1 hour, HPLC monitors raw material (N, N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide)＜0.5%.Divide the phase of anhydrating, water merges organic phase after extracting 1 time with toluene 220ml, and the salt solution washing is evaporated to dried.Get N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides crude product～170g; HPLC purity～85% (2l0nm); LC-MS:m/e=203.Contain a small amount of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid, ethyl ester.
Synthesizing of 3-difluoromethyl-1-methylpyrazole-4-formic acid
In the 1000ml reaction flask, add ethanol (85ml), N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides crude product～170g, 20% hydrochloric acid 340g, the 60 ° of C that heat up, reaction is spent the night, and HPLC monitors raw material (N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides)＜0.5%.Concentrating under reduced pressure boils off ethanol, and residual solution is cooled to room temperature, separates out solid, filters washing, the dry product～120g that gets.Purity～98%.LC-MS:m/e=176。
Embodiment 5
N, N-dimethyl difluoro aceto-acetamide synthetic
In the 1000mL reaction flask, add ethanamide 265g, be cooled to 0 ° of C, add sodium ethylate (78.2g), control 0～20 ° of C and drip ethyl difluoro (124g), behind the reaction 100min, slowly be warming up to 50 ° of C, reacted GC Monitoring and Controlling raw material (ethyl difluoro)＜1% 2 hours; Be cooled to 0～10 ° of C, slowly drip acetic acid (75g) and filter (desalination); Solid is with a small amount of washing with alcohol; Merging filtrate concentrating under reduced pressure (the control temperature is lower than 50 ° of C) is product/ethanamide mixed solution～350g without the cut resistates substantially extremely, GC content～43% (theory: 165g); LC-MS:m/e=165.
N, N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide synthetic
In the 2000mL reaction flask, suction triethyl orthoformate (267.6g), aceticanhydride (276.7g), slowly be warming up to～100 ° of C, drip N, and N-dimethyl difluoro aceto-acetamide crude product (the pure product of GC～150g), add, continue reaction 0.5 hour, GC Monitoring and Controlling raw material (N, N-dimethyl difluoro aceto-acetamide)＜0.5%; Be cooled to 50～60 ° of C, concentrating under reduced pressure, the underpressure distillation of resistates lobe pump, (removing the low impurity that boils) gets thick product～220g (＞100%); GC purity :～90%; LC-MS:m/e=221.
N, N-dimethyl-3-difluoromethyl-1H-pyrazoles-4-acid amides synthetic
In the 1000ml reaction flask, add toluene (440ml), 40% hydrazine hydrate aqueous solution (100g), room temperature～20 ° C drips N, the toluene solution (220g/220mL) of N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide, add, keep 20～25 ° of C reactions 1 hour, HPLC monitors raw material (N, N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide)＜0.5%.Divide the phase of anhydrating, water merges organic phase after extracting 1 time with toluene 220ml, and the salt solution washing is evaporated to dried.Get N, N-dimethyl-3-difluoromethyl-lH-pyrazoles-4-acid amides crude product～160g; HPLC purity～95% (2l0nm); LC-MS:m/e=189.
Synthesizing of 3-difluoromethyl-1H-pyrazoles-4-formic acid
In the 1000ml reaction flask, add ethanol (85ml), N, N-dimethyl-3-difluoromethyl-lH-pyrazoles-4-acid amides crude product～160g, the 20% hydrochloric acid 340g 60 ° of C that heat up, reaction is spent the night, HPLC monitors raw material (N, N-dimethyl-3-difluoromethyl-lH-pyrazoles-4-acid amides)＜0.5%.Concentrating under reduced pressure boils off ethanol, and residual solution is cooled to room temperature, separates out solid, filters washing, the dry product～1l0g that gets.Purity～98%.LC-MS:m/e=162。
Embodiment 6
N, N-dimethyl difluoro aceto-acetamide synthetic
In the 1000mL reaction flask, add ethanamide 100g, ethanol 200g; Be cooled to 0 ° of C, add sodium ethylate (78.2g), control 0～20 ° of C and drip ethyl difluoro (124g), behind the reaction 100min, slowly be warming up to 50 ° of C, reacted GC Monitoring and Controlling raw material (ethyl difluoro)＜2% 5 hours; Be cooled to 0～10 ° of C, slowly drip acetic acid (75g) and filter (desalination); Solid is with a small amount of washing with alcohol; Merging filtrate concentrating under reduced pressure (the control temperature is lower than 50 ° of C) is product/ethanamide mixed solution～200g without the cut resistates substantially extremely, GC content～75% (theory: 165g); LC-MS:m/e=165.Also contain 5%～10% acid amides alcoholysis product in the solution: the difluoro methyl aceto acetate.
N, N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide synthetic
In the 2000mL reaction flask, suction triethyl orthoformate (267.6g), aceticanhydride (276.7g) slowly is warming up to～100 ° of C, drips N, the N-dimethyl difluoro aceto-acetamide crude product (pure product～150g of GC; Contain a small amount of difluoro methyl aceto acetate), add, continue reaction 0.5 hour, GC Monitoring and Controlling raw material (N, N-dimethyl difluoro aceto-acetamide)＜0.5%; Be cooled to 50～60 ° of C, concentrating under reduced pressure, the underpressure distillation of resistates lobe pump, (removing the low impurity that boils) gets thick product～220g (＞100%); GC purity :～85%; LC-MS:m/e=221.Contain 2-oxyethyl group methylene radical-difluoro methyl aceto acetate.
N, N-dimethyl-3-difluoromethyl-lH-pyrazoles-4-acid amides synthetic
In the 1000ml reaction flask, add toluene (440ml), 40% hydrazine hydrate aqueous solution (100g), room temperature～20 ° C drips N, the toluene solution (220g/220mL) of N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide, add, keep 20～25 ° of C reactions 1 hour, HPLC monitors raw material (N, N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide)＜0.5%.Divide the phase of anhydrating, water merges organic phase after extracting 1 time with toluene 220ml, and the salt solution washing is evaporated to dried.Get N, N-dimethyl-3-difluoromethyl-lH-pyrazoles-4-acid amides crude product～160g; HPLC purity～95% (2l0nm); LC-MS:m/e=189.
Synthesizing of 3-difluoromethyl-lH-pyrazoles-4-formic acid
In the 1000ml reaction flask, add ethanol (85ml), N, N-dimethyl-3-difluoromethyl-1H-pyrazoles-4-acid amides crude product～170g, the 20% liquid caustic soda 340g 60 ° of C that heat up, reaction is spent the night, HPLC monitors raw material (N, N-dimethyl-3-difluoromethyl-lH-pyrazoles-4-acid amides)＜0.5%.Concentrating under reduced pressure boils off ethanol, and residual solution adds 31% hcl acidifying to pH～l, is cooled to room temperature, separates out solid, filters washing, the dry product～60g that gets.Purity～25%.LC-MS:m/e=162。
Embodiment 7
N, N-dimethyl difluoro aceto-acetamide synthetic
In the 1000mL reaction flask, add ethanamide 100g, anhydrous tetrahydro furan 200g; Be cooled to 0 ° of C, add sodium ethylate (78.2g), control 0～20 ° of C and drip ethyl difluoro (124g), behind the reaction 100min, slowly be warming up to 50 ° of C, reacted GC Monitoring and Controlling raw material (ethyl difluoro)＜2% 2 hours; Be cooled to 0～10 ° of C, slowly drip acetic acid (75g) and filter (desalination); Solid washs with a small amount of tetrahydrofuran (THF); Merging filtrate concentrating under reduced pressure (the control temperature is lower than 50 ° of C) is product/ethanamide mixed solution～190g without the cut resistates substantially extremely, GC purity～80% (theory: 165g); LC-MS:m/e=165.
N, N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide synthetic
In the 2000mL reaction flask, suction triethyl orthoformate (267.6g), aceticanhydride (276.7g), slowly be warming up to～100 ° of C, drip N, and N-dimethyl difluoro aceto-acetamide crude product (the pure product of GC～150g), add, continue reaction 0.5 hour, GC Monitoring and Controlling raw material (N, N-dimethyl difluoro aceto-acetamide)＜0.5%; Be cooled to 50～60 ° of C, concentrating under reduced pressure, the underpressure distillation of resistates lobe pump, (removing the low impurity that boils) gets thick product～220g (＞100%); GC purity :～90%; LC-MS:m/e=221.
N, N-dimethyl-3-difluoromethyl-lH-pyrazoles-4-acid amides synthetic
In the 1000ml reaction flask, add toluene (440ml), 40% hydrazine hydrate aqueous solution (100g), room temperature～20 ° C drips N, the toluene solution (220g/220mL) of N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide, add, keep 20～25 ° of C reactions 1 hour, HPLC monitors raw material (N, N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide)＜0.5%.Divide the phase of anhydrating, water merges organic phase after extracting 1 time with toluene 220ml, and the salt solution washing is evaporated to dried.Get N, N-dimethyl-3-difluoromethyl-lH-pyrazoles-4-acid amides crude product～160g; HPLC purity～95% (2l0nm); LC-MS:m/e=189.
Synthesizing of 3-difluoromethyl-1H-pyrazoles-4-formic acid
In the 1000ml reaction flask, add ethanol (85ml), N, N-dimethyl-3-difluoromethyl-lH-pyrazoles-4-acid amides crude product～160g, the 20% hydrochloric acid 340g 60 ° of C that heat up, reaction is spent the night, HPLC monitors raw material (N, N-dimethyl-3-difluoromethyl-lH-pyrazoles-4-acid amides)＜0.5%.Concentrating under reduced pressure boils off ethanol, and residual solution is cooled to room temperature, separates out solid, filters washing, the dry product～110g that gets.Purity～98%.LC-MS:m/e=162。
Embodiment 8
N, N-dimethyl difluoro aceto-acetamide synthetic
In the 1000mL reaction flask, add ethanamide 100g, anhydrous tetrahydro furan 200g; Be cooled to 0 ° of C, add sodium ethylate (78.2g), control 0～20 ° of C and drip ethyl difluoro (124g), behind the reaction 100min, slowly be warming up to 50 ° of C, reacted GC Monitoring and Controlling raw material (ethyl difluoro)＜2% 2 hours; Be cooled to 0～10 ° of C, slowly drip acetic acid (75g) and filter (desalination); Solid washs with a small amount of tetrahydrofuran (THF); Merging filtrate concentrating under reduced pressure (the control temperature is lower than 50 ° of C) is product/ethanamide mixed solution～190g without the cut resistates substantially extremely, GC purity～80% (theory: 165g); LC-MS:m/e=165.
N, N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide synthetic
In the 2000mL reaction flask, suction triethyl orthoformate (267.6g), aceticanhydride (276.7g) slowly is warming up to～100 ° of C, drips N, the N-dimethyl difluoro aceto-acetamide crude product (pure product～150g of GC; Contain a small amount of difluoro methyl aceto acetate), add, continue reaction 0.5 hour, GC Monitoring and Controlling raw material (N, N-dimethyl difluoro aceto-acetamide)＜0.5%; Be cooled to 50～60 ° of C, concentrating under reduced pressure, the underpressure distillation of resistates lobe pump, (removing the low impurity that boils) gets thick product～220g (＞100%); GC purity :～85%; LC-MS:m/e=221.Contain 2-oxyethyl group methylene radical-difluoro methyl aceto acetate.
N, N-dimethyl-3-difluoromethyl-lH-pyrazoles-4-acid amides synthetic
In the 1000ml reaction flask, add toluene (440ml), 40% hydrazine hydrate aqueous solution (100g), room temperature～20 ° C drips N, the toluene solution (220g/220mL) of N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide, add, keep 20～25 ° of C reactions 1 hour, HPLC monitors raw material (N, N-dimethyl-2-oxyethyl group methylene radical difluoro aceto-acetamide)＜0.5%.Divide the phase of anhydrating, water merges organic phase after extracting 1 time with toluene 220ml, and the salt solution washing is evaporated to dried.Get N, N-dimethyl-3-difluoromethyl-1H-pyrazoles-4-acid amides crude product～160g; HPLC purity～95% (2l0nm); LC-MS:m/e=189.
Synthesizing of 3-difluoromethyl-1H-pyrazoles-4-formic acid
In the 1000ml reaction flask, add ethanol (85ml), N, N-dimethyl-3-difluoromethyl-lH-pyrazoles-4-acid amides crude product～170g, 60C ° of 20% liquid caustic soda 340g intensification, reaction is spent the night, HPLC monitors raw material (N, N-dimethyl-3-difluoromethyl-lH-pyrazoles-4-acid amides)＜0.5%.Concentrating under reduced pressure boils off ethanol, and residual solution adds 31% hcl acidifying to pH～l, is cooled to room temperature, separates out solid, filters washing, the dry product～60g that gets.Purity～25%.LC-MS:m/e=162。
Although the present invention discloses as above with preferred embodiment; so it is not to limit the present invention; any person of ordinary skill in the field; without departing from the spirit and scope of the present invention; when can doing a little change and improvement, so protection scope of the present invention is as the criterion when looking the claim person of defining.
Claims (10)
1. 3-fluoro-alkyl-1-substituted pyrazolecarboxylic-4-carboxylic acid has following formula VI structure:
Wherein, R
1, R
2Hydrogen, fluorine atom;
R
8It is the lower paraffin hydrocarbons of H or C1～C4.
2. 3-fluoro-alkyl according to claim 1-1-substituted pyrazolecarboxylic-4-carboxylic acid, it is characterized in that described 3-fluoro-alkyl-1-substituted pyrazolecarboxylic-4-carboxylic acid is the 3-difluoromethyl shown in the 3-difluoromethyl shown in the formula VII-1-methylpyrazole-4-formic acid and/or the formula VIII-1H-pyrazoles-4-formic acid
3. the preparation method of 3-fluoro-alkyl claimed in claim 1-1-substituted pyrazolecarboxylic-4-carboxylic acid is characterized in that, comprises step:
1) take the acetamide derivative shown in the fluoro acetogenin shown in the formula I and the formula II as raw material, condensation forms the fluoro acetoacetyl sulfonamide derivatives shown in the formula III under the effect of sodium alkoxide
Wherein, R
1, R
2Hydrogen, fluorine atom;
R
3, R
4, R
5, R
6It is the lower paraffin hydrocarbons of H or C1～C4;
2) effect of the fluoro acetoacetyl sulfonamide derivatives shown in the described formula III and ortho-formiate, aceticanhydride forms the 2-alkoxyl group methylene radical fluoro acyl group acetamide derivative shown in the formula IV
Wherein, R
1, R
2Hydrogen, fluorine atom;
R
3, R
4, R
5, R
7It is the lower paraffin hydrocarbons of H or C1～C4;
3) the 2-alkoxyl group methylene radical fluoro acyl group acetamide derivative shown in the described formula IV and the cyclization of hydrazine class reagent obtain the 1-replacement-3-fluoroalkyl pyrazole shown in the formula V-4-amide derivatives
Wherein, R
1, R
2Hydrogen, fluorine atom;
R
4, R
5, R
7, R
8It is the lower paraffin hydrocarbons of H or C1～C4;
4) the 1-replacement-3-fluoroalkyl pyrazole shown in the described formula V-4-amide derivatives obtains the 3-fluoro-alkyl shown in the formula VI-1-substituted pyrazolecarboxylic-4-carboxylic acid through hydrolysis
Wherein, R
1, R
2Hydrogen, fluorine atom;
R
4, R
5, R
8It is the lower paraffin hydrocarbons of H or C1～C4.
4. method according to claim 3 is characterized in that step 1) in, the fluoro acetogenin of formula I is ethyl difluoro; The acetamide derivative of formula II is ethanamide; The fluoro acetoacetyl sulfonamide derivatives of formula III is N, N-dimethyl difluoro aceto-acetamide.
5. method according to claim 3 is characterized in that step 1) in, condensation reaction is carried out in solvent-free, organic ether kind solvent or organic alcohols solvent system, and wherein the machine ether solvent is THF or dioxane; The organic alcohols solvent is methyl alcohol or ethanol.
6. method according to claim 3 is characterized in that step 2) in, the 2-alkoxyl group methylene radical fluoro acyl group acetamide derivative of described formula IV is N, N-dimethyl-2-oxyethyl group methylene radical difluoro acetoacetyl; The mol ratio of the fluoro acetoacetyl sulfonamide derivatives of ortho-formiate and formula III is 0.8～5: 1; The mol ratio of the fluoro acetoacetyl sulfonamide derivatives of aceticanhydride and formula III is 1～6: 1.
7. method according to claim 3 is characterized in that step 3) in, reaction is carried out in varsol or organic ether kind solvent system, and wherein varsol is benzene, toluene or dimethylbenzene; The organic ether kind solvent is THF, dioxane or methyl tertiary butyl ether.
8. method according to claim 3, it is characterized in that step 3) in, the 1-replacement-3-fluoroalkyl pyrazole of described formula V-the 4-amide derivatives is N, N-dimethyl-3-difluoromethyl-1-methylpyrazole-4-acid amides and/or N, N-dimethyl-3-difluoromethyl-1H-pyrazoles-4-acid amides.
9. method according to claim 3, it is characterized in that, step 4) in, described hydrolysis reaction is with acid hydrolysis or basic hydrolysis, reaction is carried out in water or water and organic alcohols solvent system, wherein, described acid is hydrochloric acid, Hydrogen bromide or sulfuric acid: described alkali is lithium hydroxide, sodium hydroxide or potassium hydroxide, and described Organic Alcohol is methyl alcohol or ethanol.
10. method according to claim 3 is characterized in that step 1) in, condensation reaction occurs in-10 ℃～60 ℃; Step 2) reaction in occurs in 80 ℃～120 ℃; Step 3) reaction in occurs in-20 ℃～50 ℃; Step 4) reaction in occurs in 20 ℃～100 ℃.
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| WO2015058319A1 (en) * | 2013-10-23 | 2015-04-30 | 雅本化学股份有限公司 | 3-fluoroalkyl-1-substituted pyrazol-4-carboxylic acid and preparation method therefor |
| CN106554311A (en) * | 2015-09-28 | 2017-04-05 | 常州市卜弋科研化工有限公司 | The preparation method of 3- fluoro-alkyl -1- methylpyrazole -4- carboxylic acids |
| CN108368055A (en) * | 2015-09-28 | 2018-08-03 | 苏威氟有限公司 | The preparation method of 3- fluoro-alkyl -1- methylpyrazole -4- carboxylic acids |
| WO2019224677A1 (en) | 2018-05-21 | 2019-11-28 | Pi Industries Ltd. | Method for preparing substituted heterocyclic compounds |
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| CN115141147B (en) * | 2022-08-24 | 2023-09-12 | 绍兴上虞新银邦生化有限公司 | Synthesis method of N-methyl-3-substituted methyl-4-pyrazole formamide derivative |
| WO2024040995A1 (en) * | 2022-08-24 | 2024-02-29 | 绍兴上虞新银邦生化有限公司 | Synthesis method for n-methyl-3-substituted methyl-4-pyrazolecarboxamide derivative and n-methyl-3-substituted methyl-4-pyrazole formic acid |
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