WO2016202254A1 - 一种用于制备吡唑甲酸衍生物的方法及其中间体 - Google Patents

一种用于制备吡唑甲酸衍生物的方法及其中间体 Download PDF

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WO2016202254A1
WO2016202254A1 PCT/CN2016/085814 CN2016085814W WO2016202254A1 WO 2016202254 A1 WO2016202254 A1 WO 2016202254A1 CN 2016085814 W CN2016085814 W CN 2016085814W WO 2016202254 A1 WO2016202254 A1 WO 2016202254A1
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methyl
formula
pyrazole
difluoromethyl
compound
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PCT/CN2016/085814
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English (en)
French (fr)
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邵鸿鸣
何人宝
金逸中
王雷
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浙江永太科技股份有限公司
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Priority claimed from CN201510346308.6A external-priority patent/CN104945325B/zh
Priority claimed from CN201510348921.1A external-priority patent/CN104945387B/zh
Application filed by 浙江永太科技股份有限公司 filed Critical 浙江永太科技股份有限公司
Priority to ES16810995T priority Critical patent/ES2844530T3/es
Priority to US15/737,483 priority patent/US10407413B2/en
Priority to EP16810995.7A priority patent/EP3312161B1/en
Publication of WO2016202254A1 publication Critical patent/WO2016202254A1/zh

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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • the present invention relates to a process for the preparation of pyrazolecarboxylic acid derivatives and intermediates thereof.
  • Pyrazolecarboxylic acid derivatives such as 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid are key intermediates for the preparation of pesticide bactericides.
  • the document JP-2000-044541 reports that, in the presence of a base, the corresponding substituted pyrazole is di-methylated with a dialkyl carboxylic acid such as dimethyl sulfate and diethyl sulfate to obtain an N-substituted pyrazole.
  • a dialkyl carboxylic acid such as dimethyl sulfate and diethyl sulfate to obtain an N-substituted pyrazole.
  • a pyrazolecarboxylic acid derivative is obtained by a series of reactions.
  • dialkyl sulfate is difficult to apply on a large scale in large factories.
  • Chinese patent CN101044116A uses trialkyl phosphate instead of the highly toxic dialkyl sulfate, but needs to react at a high temperature of 180-200 ° C for 18-24 hours, and the post-treatment produces a large amount of wastewater, which does not meet environmental protection requirements.
  • JACS, 73, 3684 (1951) describes the preparation of (2-ethoxymethylene)-4,4 by reacting ethyl 4,4-difluoro-3-oxobutanoate with triethyl orthoformate and acetic anhydride. Ethyl difluoromethylacetoacetate, which is then reacted with an anthracene derivative to give ethyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate, which is obtained by hydrolysis.
  • the ethyl 4,4-difluoro-3-oxobutanoate used is expensive and the yield is less than 70%.
  • the technical problem to be solved by the present invention is to provide a preparation method of a simple and economical environment-friendly pyrazolecarboxylic acid derivative, which adopts a new intermediate, and has high reaction yield and exhaust gas in each step.
  • the waste water is low and the cost is low, and no special reaction equipment is needed.
  • the present invention provides a compound of the following formula (II),
  • R 1 is selected from methyl or ethyl, preferably methyl
  • R 4 is hydrogen or methyl, preferably methyl
  • n is 0-4, preferably 0 or 1;
  • X is F, Cl or CF 3 , preferably F.
  • R 1 is methyl
  • R 4 is methyl
  • n is 1
  • X is F
  • R 1 is ethyl
  • R 4 is hydrogen
  • n is 1
  • X is F
  • R 1 is methyl
  • R 4 is hydrogen
  • n is 1
  • X is F
  • R 1 is methyl
  • R 4 is methyl
  • n is 0, and X is F.
  • R 1 is ethyl
  • R 4 is hydrogen
  • n is 0, and X is F.
  • R 1 is methyl
  • R 4 is hydrogen
  • n is 0, and X is F.
  • R 1 is selected from a methyl group or an ethyl group, preferably a methyl group; and R 4 is hydrogen or a methyl group, preferably a methyl group.
  • the invention provides a process for the preparation of a compound of the above formula (II), the process comprising the steps of:
  • R 2 and R 3 are independently selected from C 1 -C 4 alkyl, preferably methyl;
  • R 4 is hydrogen or methyl, preferably methyl, and n is 0-4, preferably 0 or 1;
  • R 4 is hydrogen or methyl.
  • the 1,5-diazapentadienyl salt of formula (V) is as follows:
  • Y - is an anion selected from the group consisting of [BF 4 ] - , [AlCl 3 F] - , [AlF 4 ] - , [ZnCl 2 F] - , [SbF 6 ] - , [SnCl 4 F] - , [BiCl 3 F] - , [GaCl 3 F] - and [SiCl 4 F] - . From the corresponding Lewis acid.
  • R 2 , R 3 , R 4 and Y - are as described above.
  • the present invention provides a process for the preparation of a compound of the following formula (I),
  • R 1 is selected from methyl or ethyl, preferably methyl
  • X is F, Cl or CF 3 , preferably F;
  • the method includes the following steps:
  • R 2 and R 3 are independently selected from C 1 -C 4 alkyl, preferably methyl;
  • R 4 is hydrogen or methyl, preferably methyl, and n is 0-4, preferably 0 or 1;
  • R 4 is hydrogen or methyl, preferably methyl.
  • the 1,5-diazapentadienyl salt of formula (V) is as follows:
  • Y - is an anion selected from the group consisting of [BF 4 ] - , [AlCl 3 F] - , [AlF 4 ] - , [ZnCl 2 F] - , [SbF 6 ] - , [SnCl 4 F] - , [BiCl 3 F] - , [GaCl 3 F] - and [SiCl 4 F] - . From the corresponding Lewis acid.
  • R 2 , R 3 , R 4 and Y - are as defined above.
  • the Lewis acid in the step (1) is selected from the group consisting of BF 3 , AlCl 3 , AlF 3 , ZnCl 2 , PF 5 , SbF 5 , SnCl 4 , BiCl 3 , GaCl 3 , SiCl 4 , preferably BF 3 .
  • the reaction temperature in the step (1) may be from -20 ° C to 60 ° C, preferably from -10 ° C to 40 ° C, more preferably from 0 ° C to 30 ° C.
  • the reaction in step (1) is preferably carried out at room temperature.
  • the ⁇ -fluoroamine used in step (1) is selected from the group consisting of 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine, 1,1,2,2 -tetrafluoroethyl-N,N-diethylamine, 1,1,2-trifluoro-2-(trifluoromethyl)ethyl-N,N-dimethylamine, 1,1,2- Trifluoro-2-(trifluoromethyl)ethyl-N,N-diethylamine, 1,1,2-trifluoro-2-chloroethyl-N,N-dimethylamine and 1, 1,2-trifluoro-2-chloroethyl-N,N-diethylamine, the ⁇ -fluoroamine is preferably 1,1,2,2-tetrafluoroethyl-N,N-dimethyl Amine and 1,1,2,2-tetrafluoroethyl-N,N-diethylamine, and
  • the amount of the Lewis acid used is not particularly limited.
  • the molar ratio of the Lewis acid to the ⁇ -fluoroamine in the step (1) is between 1:1 and 10:1, preferably 1:1 to 5: 1, more preferably between 1:1 and 1.3:1.
  • the ratio of the ⁇ -fluoroamine to the ethylene derivative is between 1:10 and 10:1, preferably between 1:5 and 5:1, more preferably between 1.3:1 and 1:1.3.
  • step (2) of the aforementioned process is carried out in the presence of a solvent.
  • Suitable solvents are, for example, selected from the group consisting of aliphatic and aromatic hydrocarbons such as n-hexane, cyclohexane, benzene or toluene.
  • ethers as solvents, suitable ethers such as diethyl ether, diphenyl ether, methyl tert-butyl ether, isopropyl ethyl ether, dioxane, diglyme, dimethyl glycol or THF.
  • Nitriles can also be used as solvents, suitable nitriles such as Methyl nitrile, butyronitrile or benzonitrile.
  • the solvent is preferably selected from the group consisting of diethyl ether, acetonitrile, dichloromethane and tetrahydrofuran, with acetonitrile or tetrahydrofuran being especially preferred.
  • the hydrazine used in step (2) is methyl hydrazine or ethyl hydrazine, preferably methyl hydrazine.
  • the molar ratio of the 1,5-diazapentadienyl salt of the formula (V) to the aforementioned hydrazine in the step (2) is between 1:10 and 10:1, preferably 1:5 to Between 5:1, more preferably between 1.3:1 and 1:1.3.
  • the reaction temperature in the step (2) may be from -20 ° C to 60 ° C, preferably from -10 ° C to 40 ° C, more preferably from 0 ° C to 30 ° C.
  • the reaction in step (2) is preferably carried out at room temperature.
  • the hydrolysis reaction of the formula (II) in the step (3) is carried out in the presence of a solvent selected from the group consisting of methanol, ethanol, acetonitrile, tetrahydrofuran and the like, or a single liquid, or a single solvent.
  • a solvent selected from the group consisting of methanol, ethanol, acetonitrile, tetrahydrofuran and the like, or a single liquid, or a single solvent.
  • water is preferably used as the solvent.
  • the hydrolysis reaction can be carried out under basic or acidic conditions.
  • Acidic hydrolysis is preferred, and the acid used may be an organic or inorganic acid, preferably a mineral acid.
  • the inorganic acid may be hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid or the like, preferably hydrochloric acid or sulfuric acid.
  • the hydrolysis reaction temperature may be from 30 ° C to 100 ° C, preferably from 30 ° C to 70 ° C, more preferably from 50 ° C to 60 ° C.
  • the molar ratio of the compound of the formula (II) to the acid may be an excess of the acid, for example, the molar ratio of the compound of the formula (II) to the acid is between 1:2 and 1:10, preferably 1:3. Between 1:5, more preferably between 1:2 and 1:3.
  • the oxidizing agent used in the oxidation reaction may be hydrogen peroxide, sodium hypochlorite, potassium permanganate, sodium chlorate, potassium chlorate or the like, preferably hydrogen peroxide or sodium hypochlorite.
  • the oxidizing agent is used in excess.
  • the oxidation reaction is carried out in the same solvent as the hydrolysis reaction, the solvent being selected from the group consisting of methanol, ethanol, acetonitrile, tetrahydrofuran and the like, or a single water as a solvent, preferably water as a solvent. .
  • the hydrolysis reaction and the oxidation reaction are continuously carried out, and the oxidizing agent is used in an amount of from 1:2 to 1:10 moles, preferably from 1:3 to 1:5 moles, per mole of the compound of the formula (II). More preferably, it is 1:2 to 1:3 mol.
  • the reaction temperature may be from 30 ° C to 100 ° C, preferably from 50 ° C to 100 ° C, more preferably from 70 ° C to 100 ° C.
  • Figure 1 1 H NMR analysis of 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3-dioxobutan-2-yl)-1H-pyrazole.
  • Figure 2 1 H NMR analysis of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid.
  • Figure 3 1 H NMR analysis of 3-(difluoromethyl)-1-methyl-4-(1,3-dioxobutan-2-yl)-1H-pyrazole.
  • Figure 4 1 H NMR analysis of 3-(difluoromethyl)-1-methyl-4-(1,3-dioxolan-2-yl)-1H-pyrazole.
  • Figure 5 1 H NMR analysis of 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3-dioxopentan-2-yl)-1H-pyrazole.
  • Figure 6 1 H NMR analysis of 3-(difluoromethyl)-1-ethyl-4-(2-methyl-1,3-dioxolan-2-yl)-1H-pyrazole.
  • Figure 7 1 H NMR analysis of 3-difluoromethyl-1-ethyl-1H-pyrazole-4-carboxylic acid.
  • Figure 8 1 H NMR analysis of 3-(difluoromethyl)-1-ethyl-4-(1,3-dioxolan-2-yl)-1H-pyrazole.
  • Figure 9 1 H NMR analysis of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-ethanone.
  • Figure 10 1 H NMR analysis of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-acetaldehyde.
  • Figure 11 1 H NMR analysis of 3-(difluoromethyl)-1-ethyl-1H-pyrazole-4-ethanone.
  • Figure 12 1 H NMR analysis of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-acetaldehyde.
  • Figure 13 1 H NMR analysis of 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3-dioxan-2-yl)-1H-pyrazole.
  • Figure 14 1 H NMR analysis of 3-(difluoromethyl)-1-methyl-4-(1,3-dioxan-2-yl)-1H-pyrazole.
  • Figure 15 1 H NMR analysis of 3-(difluoromethyl)-1-ethyl-4-(2-methyl-1,3-dioxohexane-2-yl)-1H-pyrazole.
  • Figure 16 1 H NMR analysis of 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3-dioxoheptan-2-yl)-1H-pyrazole.
  • Figure 17 1H NMR analysis of 3-(difluoromethyl)-1-methyl-4-(1,3-dioxoheptan-2-yl)-1H-pyrazole.
  • Figure 18 1 H NMR analysis of 3-(difluoromethyl)-1-ethyl-4-(2-methyl-1,3-dioxoheptan-2-yl)-1H-pyrazole.
  • the obtained reaction liquid was distilled under reduced pressure at 60 ° C or lower to recover acetonitrile. Add 250g of hot water at 50-60 °C. Stir slowly, cool to 0 ° C, precipitate crystals, and the crystallization time is 1-2 hours. Filter by suction, wash with water, and drain. Drying gave the product 75 g, purity HPLC 99.3%, yield 93.3% (m.p.).
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3-dioxane- 2-yl)-1H-pyrazole.
  • the obtained reaction liquid was distilled under reduced pressure at 60 ° C or lower to recover acetonitrile. Add 250g of hot water at 50-60 °C. Stir slowly, cool to 0 ° C, precipitate crystals, and the crystallization time is 1-2 hours. Filter by suction, wash with water, and drain. Drying gave the product 74.3 g, mp.
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3-dioxane- 2-yl)-1H-pyrazole.
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-(difluoromethyl)-1-methyl-4-(1,3-dioxobutan-2-yl)- 1H-pyrazole.
  • Mass spectrometry m/z: 190.06 (100.0%), 191.06 (7.7%).
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-(difluoromethyl)-1-methyl-4-(1,3-dioxopentan-2-yl)- 1H-pyrazole.
  • Example 2 Repeating the preparation of 3-difluoro in Example 1 using 3-(difluoromethyl)-1-methyl-4-(1,3-dioxolan-2-yl)-1H-pyrazole as an intermediate The process of methyl-1-methyl-1H-pyrazole-4-carboxylic acid to 3-(difluoromethyl)-1-methyl-4-(1,3-dioxolan-2-yl) Based on -1H-pyrazole, the molar yield was calculated and the yield was 91.4%. The obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid.
  • reaction liquid was distilled under reduced pressure at 60 ° C or lower to recover tetrahydrofuran. Try to evaporate the tetrahydrofuran. Add 500g of hot water at 50-60 °C. Stir slowly and cool to 0 ° C to precipitate crystals. Crystallization was carried out at around 0 ° C for 1-2 hours. Filter by suction, wash with water, and drain. Drying gave 150 g of product, purity HPLC 99.5% yield 91.6% (m.p. yields from N-1,1,2,2-tetrafluoroethyl dimethylamine).
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-(difluoromethyl)-1-methyl-4-(1,3-dioxopentan-2-yl)- 1H-pyrazole.
  • the obtained reaction liquid was distilled under reduced pressure at 60 ° C or lower to recover tetrahydrofuran. Try to evaporate the tetrahydrofuran. Add 500g of hot water at 50-60 °C. Stir slowly and cool to 0 ° C to precipitate crystals. Crystallization was carried out at around 0 ° C for 1-2 hours. Filter by suction, wash with water, and drain. Drying gave 155 g of product, mp. The obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the product obtained was 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3-dioxolane- 2-yl)-1H-pyrazole.
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-(difluoromethyl)-1-ethyl-4-(2-methyl-1,3-dioxolane- 2-yl)-1H-pyrazole.
  • the structure is as follows:
  • Example 6 Repeating Example 6 with 3-(difluoromethyl)-1-ethyl-4-(2-methyl-1,3-dioxolan-2-yl)-1H-pyrazole as an intermediate Process for the preparation of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid to 3-(difluoromethyl)-1-ethyl-4-(2-methyl-1,3 The molar yield was calculated on the basis of -dioxolan-2-yl)-1H-pyrazole, and the yield was 91.5%.
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-difluoromethyl-1-ethyl-1H-pyrazole-4-carboxylic acid.
  • the elemental and mass spectrometric results of the final product are as follows:
  • Mass spectrometry m/z: 190.06 (100.0%), 191.06 (7.7%).
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the product obtained was 3-(difluoromethyl)-1-ethyl-4-(1,3-dioxolan-2-yl)- 1H-pyrazole.
  • the structure is as follows:
  • the reaction was kept at 20 ° C for 2 hours. After the end of the heat preservation, the temperature was lowered to about 5 ° C, and a solution of methyl hydrazine in acetonitrile (containing 1.2 equivalents of hydrazine relative to 1,5-diazapentadienyl salt) was added dropwise, and the addition was completed in about 30 minutes. The temperature was slowly raised to 20 ° C, and the reaction was kept for 2 hours. The obtained reaction liquid was distilled under reduced pressure at 60 ° C or lower to recover acetonitrile. Add 250g of hot water at 50-60 °C. Stir slowly, cool to 0 ° C, precipitate crystals, and the crystallization time is 1-2 hours.
  • the reaction was kept at 20 ° C for 2 hours. After the end of the heat preservation, the temperature was lowered to about 5 ° C, and a solution of methyl hydrazine in acetonitrile (in which 1 equivalent of hydrazine was contained with respect to 1,5-diazapentadienyl salt) was added dropwise, and the addition was completed in about 30 minutes. The temperature was slowly raised to 20 ° C, and the reaction was kept for 2 hours. The obtained reaction liquid was distilled under reduced pressure at 60 ° C or lower to recover acetonitrile. Add 600g of hot water at 50-60 °C. Stir slowly, cool to 0 ° C, precipitate crystals, and the crystallization time is 1-2 hours.
  • Mass spectrometry m/z: 160.04 (100.0%), 161.05 (8.3%).
  • Example 9 The procedure for preparing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-ethanone in Example 9 was repeated except that the ethyl hydrazine acetonitrile solution was used instead of the methyl hydrazine acetonitrile solution. Further, the molar yield was calculated from N-1,1,2,2-tetrafluoroethyldimethylamine, and the yield was 91.4%. The obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-(difluoromethyl)-1-ethyl-1H-pyrazole-4-ethyl ketone.
  • Example 9 The 3-difluoromethyl-1-methyl-1H-pyrazole prepared in Example 9 was repeated using 3-(difluoromethyl)-1-ethyl-1H-pyrazole-4-ethanone as an intermediate.
  • the procedure of -4-carboxylic acid was carried out on the basis of 3-(difluoromethyl)-1-ethyl-1H-pyrazole-4-ethanone, and the molar yield was calculated to be 91.5%.
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-difluoromethyl-1-ethyl-1H-pyrazole-4-carboxylic acid.
  • Example 10 Preparation of 3-difluoromethyl-1-methyl-1H-pyrazole in Example 10 was carried out using 3-(difluoromethyl)-1-ethyl-1H-pyrazole-4-acetaldehyde as an intermediate.
  • the procedure of -4-carboxylic acid was carried out on the basis of 3-(difluoromethyl)-1-ethyl-1H-pyrazole-4-acetaldehyde, and the molar yield was calculated to be 94.1%.
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-difluoromethyl-1-ethyl-1H-pyrazole-4-carboxylic acid.
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the product obtained was 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3-dioxane- 2-yl)-1H-pyrazole.
  • the structure is as follows:
  • Example 2 Repeating Example 2 with 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3-dioxohexane-2-yl)-1H-pyrazole as an intermediate Process for the preparation of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid to 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3
  • the molar yield was calculated on the basis of 2-dioxan-2-yl)-1H-pyrazole, and the yield was 92.3%.
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid.
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-(difluoromethyl)-1-methyl-4-(1,3-dioxan-2-yl)- 1H-pyrazole.
  • the structure is as follows:
  • Example 5 Repeating the preparation of 3-difluoro in Example 5 using 3-(difluoromethyl)-1-methyl-4-(1,3-dioxan-2-yl)-1H-pyrazole as an intermediate Process for methyl-1-methyl-1H-pyrazole-4-carboxylic acid, 3-(difluoromethyl)-1-methyl-4-(1,3-dioxan-2-yl)- Based on 1H-pyrazole, the molar yield was calculated and the yield was 91.6%. The obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid.
  • N,N-dimethyl-2-(2-methyl-1,3-dioxan-2-yl)-ethylene instead of N,N-dimethyl-2-(2-methyl- 1,3-Dioxetane-2-yl)-ethylene
  • the preparation of 3-(difluoromethyl)- was repeated except that a solution of ethyl hydrazine in tetrahydrofuran was used instead of methyl hydrazine in acetonitrile.
  • Example 2 Repeating Example 2 with 3-(difluoromethyl)-1-ethyl-4-(2-methyl-1,3-dioxan-2-yl)-1H-pyrazole as an intermediate Process for the preparation of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid to 3-(difluoromethyl)-1-ethyl-4-(2-methyl-1,3
  • the molar yield was calculated on the basis of 2-dioxan-2-yl)-1H-pyrazole, and the yield was 92.2%.
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-difluoromethyl-1-ethyl-1H-pyrazole-4-carboxylic acid.
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3-dioxoheptane - 2-yl)-1H-pyrazole.
  • the structure is as follows:
  • Example 2 Repeating Example 2 with 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3-dioxoheptan-2-yl)-1H-pyrazole as an intermediate Process for the preparation of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid to 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3
  • the molar yield was calculated on the basis of -dioxoheptan-2-yl)-1H-pyrazole, and the yield was 92.0%.
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid.
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-(difluoromethyl)-1-methyl-4-(1,3-dioxoheptan-2-yl)- 1H-pyrazole.
  • the structure is as follows:
  • N,N-dimethyl-2-(2-methyl-1,3-dioxoheptan-2-yl)-ethylene instead of N,N-dimethyl-2-(2-methyl- 1,3-Dioxetane-2-yl)-ethylene
  • the preparation of 3-(difluoromethyl)- was repeated except that a solution of ethyl hydrazine in tetrahydrofuran was used instead of methyl hydrazine in acetonitrile.
  • Mass spectrometry m/z: 260.13 (100.0%), 261.14 (13.3%), 262.14 (1.2%).
  • Example 2 Repeating Example 2 with 3-(difluoromethyl)-1-ethyl-4-(2-methyl-1,3-dioxoheptan-2-yl)-1H-pyrazole as an intermediate Process for the preparation of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid to 3-(difluoromethyl)-1-ethyl-4-(2-methyl-1,3
  • the molar yield was calculated on the basis of -dioxoheptan-2-yl)-1H-pyrazole, and the yield was 92.1%.
  • the obtained product was subjected to 1 H NMR analysis, elemental analysis and mass spectrometry to confirm that the obtained product was 3-difluoromethyl-1-ethyl-1H-pyrazole-4-carboxylic acid.

Abstract

一种适宜于工业化生产的合成下式（I）的吡唑甲酸衍生物的制备方法以及下式（II）所示的中间体，该方法各步反应收率高，废气、废水少且成本低，无需特殊反应设备。

Description

一种用于制备吡唑甲酸衍生物的方法及其中间体 技术领域
本发明涉及一种用于制备吡唑甲酸衍生物的方法及其中间体。
背景技术
吡唑甲酸衍生物，如3-二氟甲基-1-甲基-1H-吡唑-4-羧酸是用于制备农药杀菌剂的关键中间体。
文献JP-2000-044541报道，在碱存在下，相应的取代吡唑与羧酸二烷基酯如硫酸二甲酯，硫酸二乙酯进行N-甲基化，得N-取代吡唑，再经一系列反应得到吡唑甲酸衍生物。但是硫酸二烷基酯由于其毒性，大工厂上难以大规模应用。
中国专利CN101044116A采用磷酸三烷基酯代替剧毒的硫酸二烷基酯，但是需要在高温180-200℃下，反应18-24小时，且后处理产生大量废水，不符合环保要求。
JACS，73,3684(1951)描述，将4,4-二氟-3-氧丁酸乙酯与原甲酸三乙酯和醋酐反应制备(2-乙氧基亚甲基)-4,4-二氟甲基乙酰乙酸乙酯，再与肼衍生物反应得到3-二氟甲基-1-甲基-1H-吡唑-4-羧酸乙酯，再经水解得到。但是所用的4,4-二氟-3-氧丁酸乙酯价格昂贵且收率低于70％。
如上现有工艺均存在使用毒性原料、废物难以处理导致污染环境等问题。
发明内容
针对现有技术中存在的上述问题，本发明所要解决的技术问题是提供一种简单经济环保的吡唑甲酸衍生物的制备方法，该方法采用新的中间体，各步反应收率高，废气，废水少且成本低，无需特殊反应设备。
根据本发明，上述目的通过如下实施方案实现。
根据本发明的一个实施方案，本发明提供了一种下式(II)化合物，
Figure PCTCN2016085814-appb-000001
其中
R1选自甲基或乙基，优选甲基；
R4为氢或甲基，优选甲基；
n为0-4，优选0或1；
X为F、Cl或CF3，优选F。
根据本发明的一个实施方案，R1为甲基，R4为甲基，n为1，X为F。
根据本发明的一个实施方案，R1为乙基，R4为氢，n为1，X为F。
根据本发明的一个实施方案，R1为甲基，R4为氢，n为1，X为F。
根据本发明的一个实施方案，R1为甲基，R4为甲基，n为0，X为F。
根据本发明的一个实施方案，R1为乙基，R4为氢，n为0，X为F。
根据本发明的一个实施方案，R1为甲基，R4为氢，n为0，X为F。
根据本发明的一个实施方案，式(II)化合物中n＝0时，式(II)化合物结构如下所示：
Figure PCTCN2016085814-appb-000002
此时，R1选自甲基或乙基，优选甲基；R4为氢或甲基，优选甲基。
根据本发明的一个实施方案，本发明提供了前述式(II)化合物的制备方法，所述方法包括以下步骤：
(1)在路易斯酸的存在下，将式(III)的α-氟胺与式(IV)的乙烯衍生物反应，生成式(V)的vinamidinium盐(即1,5-二氮杂戊二烯盐)，
式(III)的α-氟胺如下所示：
Figure PCTCN2016085814-appb-000003
其中X的定义如前所述，R2和R3独立地选自C1-C4烷基，优选甲基；
式(IV)的乙烯衍生物如下所示：
Figure PCTCN2016085814-appb-000004
其中R4为氢或甲基，优选甲基，n为0-4，优选0或1；
并且其中当n＝0时，式(IV)的乙烯衍生物如下所示：
Figure PCTCN2016085814-appb-000005
其中R4为氢或甲基。
式(V)的1,5-二氮杂戊二烯盐如下所示：
Figure PCTCN2016085814-appb-000006
其中n、R2和R3、R4的定义如前所述，Y-为阴离子，所述阴离子选自[BF4]-、[AlCl3F]-、[AlF4]-、[ZnCl2F]-、[SbF6]-、[SnCl4F]-、[BiCl3F]-、[GaCl3F]-和[SiCl4F]-。来自相应的路易斯酸。
并且其中当n＝0时，式(V)的1,5-二氮杂戊二烯盐如下所示：
Figure PCTCN2016085814-appb-000007
R2、R3、R4和Y-的定义如前所述。
(2)式(V)的1,5-二氮杂戊二烯盐与肼反应，得到式(II)的化合物。
根据本发明的一个实施方案，本发明提供了一种以下式(I)化合物的制备方法，
Figure PCTCN2016085814-appb-000008
其中R1选自甲基或乙基，优选甲基；
X为F、Cl或CF3，优选F；
所述方法包括以下步骤：
(1)在路易斯酸的存在下，将式(III)的α-氟胺与式(IV)的乙烯衍生物反应，生成式(V)的vinamidinium盐(即1,5-二氮杂戊二烯盐)，
式(III)的α-氟胺如下所示：
Figure PCTCN2016085814-appb-000009
其中X的定义如前所述，R2和R3独立地选自C1-C4烷基，优选甲基；
式(IV)的乙烯衍生物如下所示：
Figure PCTCN2016085814-appb-000010
其中R4为氢或甲基，优选甲基，n为0-4，优选0或1；
并且其中当n＝0时，式(IV)的乙烯衍生物如下所示：
Figure PCTCN2016085814-appb-000011
其中R4为氢或甲基，优选甲基。
式(V)的1,5-二氮杂戊二烯盐如下所示：
Figure PCTCN2016085814-appb-000012
其中n、R2和R3、R4的定义如前所述，Y-为阴离子，所述阴离子选自[BF4]-、[AlCl3F]-、[AlF4]-、[ZnCl2F]-、[SbF6]-、[SnCl4F]-、[BiCl3F]-、[GaCl3F]-和[SiCl4F]-。来自相应的路易斯酸。
并且其中当n＝0时，式(V)的1,5-二氮杂戊二烯盐如下所示：
Figure PCTCN2016085814-appb-000013
Figure PCTCN2016085814-appb-000014
其中R2、R3、R4和Y-的定义如前所述。
(2)式(V)的1,5-二氮杂戊二烯盐与肼反应，得到式(II)的化合物，
式(II)的化合物如下所示：
Figure PCTCN2016085814-appb-000015
其中X、n、R1和R4的定义如前所述；
并且其中，n＝0时，式(II)化合物结构如下所示：
Figure PCTCN2016085814-appb-000016
其中X、R1和R4的定义如前所述；
(3)n＝1-4的式(II)的化合物经过水解和氧化，或者n＝0的式(II)的化合物经过氧化，得到式(I)的化合物。
根据本发明的一个实施方案，步骤(1)中路易斯酸选自BF3、AlCl3、AlF3、ZnCl2、PF5、SbF5、SnCl4、BiCl3、GaCl3、SiCl4的化合物，优选BF3。
根据本发明的一个实施方案，步骤(1)中反应温度可在-20℃至60℃，优选-10℃至40℃，更优选0℃-30℃。由于经济原因，步骤(1)中反应优选在室温下实施。
根据本发明的一个实施方案，步骤(1)中使用的α-氟胺选自1,1,2,2-四氟乙基-N,N-二甲基胺、1,1,2,2-四氟乙基-N,N-二乙基胺、1,1,2-三氟-2-(三氟甲基)乙基-N,N-二甲基胺、1,1,2-三氟-2-(三氟甲基)乙基-N,N-二乙基胺、1,1,2-三氟-2-氯代乙基-N,N-二甲基胺和1,1,2-三氟-2-氯代乙基-N,N-二乙基胺，所述α-氟胺优选1,1,2,2-四氟乙基-N,N-二甲基胺和1,1,2,2-四氟乙基-N,N-二乙基胺，并且特别优选1,1,2,2-四氟乙基-N,N-二甲基胺。
路易斯酸的使用量无需特别限定，根据本发明的一个实施方案，步骤(1)中路易斯酸与α-氟胺的摩尔比在1:1至10:1之间，优选1:1至5:1，更优选1:1至1.3:1之间。α-氟胺与乙烯衍生物的比例在1:10至10:1之间，优选1:5至5:1之间，更优选1.3:1至1:1.3之间。
根据本发明的一个实施方案，前述方法步骤(2)在溶剂的存在下进行反应。合适的溶剂例如选自脂肪族的和芳香族的烃，例如正己烷、环己烷、苯或甲苯。被氟和氯原子取代的脂肪族的和芳香族的烃，例如二氯甲烷、二氯甲烷、三氯甲烷、四氯化碳、氟代苯、氯代苯或二氯代苯。还可使用醚作为溶剂，合适的醚例如二乙醚、二苯醚、甲基叔丁基醚、异丙基乙基醚、二噁烷、二甘醇二甲醚、二甲基乙二醇或THF。还可使用腈作为溶剂，合适的腈例如 甲基腈、丁腈或苯腈。所述溶剂优选选自乙醚、乙腈、二氯甲烷和四氢呋喃，尤其优选乙腈或四氢呋喃。
根据本发明的一个实施方案，步骤(2)中使用的肼为甲基肼或乙基肼，优选甲基肼。
根据本发明的一个实施方案，步骤(2)中式(V)的1,5-二氮杂戊二烯盐与前述肼的摩尔比在1:10至10:1之间，优选1:5至5:1之间，更优选1.3:1至1:1.3之间。
根据本发明的一个实施方案，步骤(2)中反应温度可在-20℃至60℃，优选-10℃至40℃，更优选0℃-30℃。由于经济原因，步骤(2)中反应优选在室温下实施。
根据本发明的一个实施方案，步骤(3)中式(II)的水解反应在溶剂的存在下进行，水解反应使用的溶剂选自甲醇、乙醇、乙腈、四氢呋喃等与水的混合液，或使用单一的水作为溶剂，优选使用水作溶剂。
根据本发明的一个实施方案，水解反应可在碱性或酸性的条件下进行。优选酸性水解，所用的酸可为有机酸或无机酸，优选无机酸。无机酸可为盐酸、硫酸、氢溴酸、磷酸等，优选盐酸或硫酸。水解反应温度可在30℃至100℃，优选30℃至70℃，更优选50℃-60℃。在酸的存在下进行水解时，式(II)化合物与酸的摩尔比可为酸过量，例如式(II)化合物与酸的摩尔比在1:2至1:10之间，优选1:3至1:5之间，更优选1:2至1:3之间。
根据本发明的一个实施方案，氧化反应中使用的氧化剂可为双氧水、次氯酸钠、高锰酸钾、氯酸钠、氯酸钾等，优选双氧水或次氯酸钠。氧化反应中，氧化剂过量使用。
根据本发明的一个实施方案，氧化反应在水解反应相同的溶剂中进行，所述溶剂选自甲醇、乙醇、乙腈、四氢呋喃等与水的混合液，或单一的水作溶剂，优选为水作溶剂。
根据本发明的一个实施方案，水解反应和氧化反应连续进行，基于每摩尔式(II)化合物的量，氧化剂的用量为1:2至1:10摩尔，优选1:3至1:5摩尔，更优选1:2至1:3摩尔。氧化反应中，反应温度可在30℃至100℃，优选50℃至100℃，更优选70℃至100℃。
附图说明
图1：3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧丁烷-2-基)-1H-吡唑的1H NMR分析图谱。
图2：3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的1H NMR分析图谱。
图3：3-(二氟甲基)-1-甲基-4-(1,3-二氧丁烷-2-基)-1H-吡唑的1H NMR分析图谱。
图4：3-(二氟甲基)-1-甲基-4-(1,3-二氧戊烷-2-基)-1H-吡唑的1H NMR分析图谱。
图5：3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧戊烷-2-基)-1H-吡唑的1H NMR分析图谱。
图6：3-(二氟甲基)-1-乙基-4-(2-甲基-1,3-二氧戊烷-2-基)-1H-吡唑的1H NMR分析图谱。
图7：3-二氟甲基-1-乙基-1H-吡唑-4-甲酸的1H NMR分析图谱。
图8：3-(二氟甲基)-1-乙基-4-(1,3-二氧戊烷-2-基)-1H-吡唑的1H NMR分析图谱。
图9：3-(二氟甲基)-1-甲基-1H-吡唑-4-乙酮的1H NMR分析图谱。
图10：3-(二氟甲基)-1-甲基-1H-吡唑-4-乙醛的1H NMR分析图谱。
图11：3-(二氟甲基)-1-乙基-1H-吡唑-4-乙酮的1H NMR分析图谱。
图12：3-(二氟甲基)-1-甲基-1H-吡唑-4-乙醛的1H NMR分析图谱。
图13：3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧己烷-2-基)-1H-吡唑的1H NMR分析图谱。
图14：3-(二氟甲基)-1-甲基-4-(1,3-二氧己烷-2-基)-1H-吡唑的1H NMR分析图谱。
图15：3-(二氟甲基)-1-乙基-4-(2-甲基-1,3-二氧己烷-2-基)-1H-吡唑的1H NMR分析图谱。
图16：3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧庚烷-2-基)-1H-吡唑的1H NMR分析图谱。
图17：3-(二氟甲基)-1-甲基-4-(1,3-二氧庚烷-2-基)-1H-吡唑的1H NMR分析图谱。
图18：3-(二氟甲基)-1-乙基-4-(2-甲基-1,3-二氧庚烷-2-基)-1H-吡唑的1H NMR分析图谱。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，本发明用以下具体实施例进行说明，以下所述仅仅用于解释本发明，并不能因此而理解为对本发明专利范围的限制。
应当指出的是，凡在本发明的精神和原则之内所做的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
实施例1：3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的合成
Figure PCTCN2016085814-appb-000017
向设置有搅拌装置和温度计的1000ml四口瓶中投入N-1,1,2,2-四氟乙基二甲基胺70g(0.48mol)和乙腈300g，然后在20℃滴加BF3乙腈溶液150g(其中相对于使用的N-1,1,2,2-四氟乙基二甲基胺，含有1.2当量的BF3)，滴加时间为15-30min，搅拌30min。滴加N,N-二甲基-2-(2-甲基-1,3-二氧丁烷-2-基)-乙烯81.8g(0.58mol)，30min滴加完毕。20℃下保温反应2小时。保温结束后降温至5℃左右，滴加甲基肼的乙腈溶液(其中相对于1,5-二氮杂戊二烯盐，含有1.1当量的肼)，30min左右滴加完毕。慢慢升温至20℃，保温反应2小时。所得反应液60℃以下减压蒸馏回收乙腈。加入50-60℃热水250g。慢慢搅拌，降温至0℃，析出结晶，析晶时间为1-2小时。抽滤，水洗，抽干。干燥，得到产物75g，纯度HPLC 99.3％，收率93.3％(以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率)。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧丁烷-2-基)-1H-吡唑。
Figure PCTCN2016085814-appb-000018
并且产物的元素分析和质谱分析结果如下：
质谱分析：m/z:204.07(100.0％),205.07(9.4％)。
元素分析：C,47.06；H,4.94；F,18.61；N,13.72；O,15.67。
向设置有搅拌装置和温度计的2000ml四口瓶中投入前述化合物(II)75g，水300g，30％盐酸100g(0.82mol)，升温至50-60℃水解反应5h，滴加10％次氯酸钠溶液480g(0.65mol)，升温至100℃，回流反应5h，慢慢降温至10℃，析晶2h，抽滤，水洗，抽干。干燥，得到产物57.70g，纯度HPLC 99.5％收率91.3％(以化合物II计算摩尔收率)。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-二氟甲基-1-甲基-1H-吡唑-4-甲酸。
最终产物的元素分析和质谱分析结果如下：
质谱分析：m/z:176.04(100.0％),177.04(7.3％)。
元素分析：C,40.92；H,3.43；F,21.57；N,15.91；O,18.17。
实施例2：3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的合成
Figure PCTCN2016085814-appb-000019
向设置有搅拌装置和温度计的1000ml四口瓶中投入N-1,1,2,2-四氟乙基二甲基胺73g(0.50mol)，乙腈300g。0℃下滴加BF3乙腈溶液180g(其中相对于使用的N-1,1,2,2-四氟乙基二甲基胺，含有1.3当量的BF3)，滴加时间为15-30min。常温搅拌30min。滴加N,N-二甲基-2-(2-甲基-1,3-二氧丁烷-2-基)-乙烯78g(0.55mol)，30min滴加完毕。30℃下保温反应2小时。保温结束后降温至5℃左右。滴加甲基肼的乙腈溶液(其中相对于1,5-二氮杂戊二烯盐，含有1.1当量的肼)，30min左右滴加完毕。慢慢升温至30℃，保温反应2小时。所得反应液60℃以下减压蒸馏回收乙腈。加入50-60℃热水250g。慢慢搅拌，降温至0℃，析出结晶，析晶时间为1-2小时。抽滤，水洗，抽干。干燥，得到产物74.3g，纯度HPLC 99.1％收率91.6％(以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率)。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧丁烷-2-基)-1H-吡唑。
Figure PCTCN2016085814-appb-000020
并且3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧丁烷-2-基)-1H-吡唑的元素分析和质谱分析结果如下：质谱：m/z:204.07(100.0％),205.07(9.4％)。
元素分析：C,47.06；H,4.94；F,18.61；N,13.72；O,15.67。
向设置有搅拌装置和温度计的1000ml四口瓶中投入3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧丁烷-2-基)-1H-吡唑74.3g，水300g，30％盐酸90g(0.74mol)，升温至50-60℃，水解反应5h，滴加30％双氧水80g(0.70mol)，升温至100℃，回流反应5h，慢慢降温至10℃，析晶2h，抽滤，水洗，抽干。干燥，得到产物60g，纯度HPLC 99.5％收率95.2％(以化合物II计算摩尔收率)。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-二氟甲基-1-甲基-1H-吡唑-4-甲酸。
实施例3：3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的合成
Figure PCTCN2016085814-appb-000021
除了使用0.58mol的N,N-二甲基-2-(1,3-二氧丁烷-2-基)-乙烯代替实施例1中的N,N-二甲基-2-(2-甲基-1,3-二氧丁烷-2-基)-乙烯以外，重复实施例1中制备3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧丁烷-2-基)-1H-吡唑的过程，并且以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率，收率为90.0％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-甲基-4-(1,3-二氧丁烷-2-基)-1H-吡唑。
Figure PCTCN2016085814-appb-000022
并且产物的元素分析和质谱分析结果如下：
质谱分析：m/z:190.06(100.0％),191.06(7.7％)。
元素分析：C,44.22；H,4.24；F,19.98；N,14.73；O,16.83。
以3-(二氟甲基)-1-甲基-4-(1,3-二氧丁烷-2-基)-1H-吡唑为中间体，重复实施例1中制备3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的过程，以3-(二氟甲基)-1-甲基-4-(1,3-二氧丁烷-2-基)-1H-吡唑为基准，计算摩尔收率，收率为91.0％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-二氟甲基-1-甲基-1H-吡唑-4-甲酸。
实施例4：3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的合成
Figure PCTCN2016085814-appb-000023
除了使用0.58mol的N,N-二甲基-2-(1,3-二氧戊烷-2-基)-乙烯代替实施例1中的N,N-二甲基-2-(2-甲基-1,3-二氧丁烷-2-基)-乙烯以外，重复实施例1中制备3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧丁烷-2-基)-1H-吡唑的过程，并且以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率，收率为90.4％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-甲基-4-(1,3-二氧戊烷-2-基)-1H-吡唑。
Figure PCTCN2016085814-appb-000024
并且产物的元素分析和质谱分析结果如下：
质谱分析：m/z:204.07(100.0％),205.07(9.4％)。
元素分析：C,47.06；H,4.94；F,18.61；N,13.72；O,15.67。
以3-(二氟甲基)-1-甲基-4-(1,3-二氧戊烷-2-基)-1H-吡唑为中间体，重复实施例1中制备3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的过程，以3-(二氟甲基)-1-甲基-4-(1,3-二氧戊烷-2-基)-1H-吡唑为基准，计算摩尔收率，收率为91.4％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-二氟甲基-1-甲基-1H-吡唑-4-甲酸。
实施例5：3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的合成
Figure PCTCN2016085814-appb-000025
向设置有搅拌装置和温度计的2000ml四口瓶中投入N-1,1,2,2-四氟乙基二甲基胺150g(1.03mol)，四氢呋喃800g。然后在0℃下滴加BF3四氢呋喃溶液350g(其中相对于使用的N-1,1,2,2-四氟乙基二甲基胺，含有1.3当量的BF3)，滴加时间为15-30min。常温搅拌30min。再滴加N,N-二甲基-2-(1,3-二氧戊烷-2-基)-乙烯175g(1.13mol)，30min滴加完毕。0℃下保温反应2小时。保温结束后升温至5℃左右，滴加甲基肼的四氢呋喃溶液(其中相对于1,5-二氮杂戊二烯盐，含有1.3当量的肼)，30min左右滴加完毕。慢慢升温至20℃，保温反应2小时。所得反应液60℃以下减压蒸馏回收四氢呋喃。尽量蒸干四氢呋喃。加入50-60℃热水500g。慢慢搅拌，降温至0℃，析出结晶。0℃左右析晶1-2小时。抽滤，水洗，抽干。干燥，得到产物150g，纯度HPLC 99.5％收率91.6％(以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率)。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-甲基-4-(1,3-二氧戊烷-2-基)-1H-吡唑。
于2000ml四口瓶中安装搅拌，温度计。投入化合物3-(二氟甲基)-1-甲基-4-(1,3-二氧戊烷-2-基)-1H-吡唑150g，水600g，30％盐酸150g(1.23mol)，升温至50-60℃，水解反应5h，滴加30％双氧水150g(1.32mol)，升温至100℃，回流反应5h，慢慢降温至10℃，析晶2h，抽滤，水洗，抽干。干燥，得到产物120g，纯度HPLC 99.2％收率93.2％(以化合物II计算摩尔收率)。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-二氟甲基-1-甲基-1H-吡唑-4-甲酸。
实施例6：3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的合成
Figure PCTCN2016085814-appb-000026
向设置有搅拌装置和温度计的2000ml四口瓶中投入N-1,1,2,2-四氟乙基二甲基胺 145g(1.0mol)，四氢呋喃700g，然后在0℃下滴加BF3四氢呋喃溶液350g(其中相对于使用的N-1,1,2,2-四氟乙基二甲基胺，含有1.3当量的BF3)，滴加时间为15-30min。常温搅拌30min。再滴加N,N-二甲基-2-(2-甲基1,3-二氧戊烷-2-基)-乙烯185g(1.20mol)，30min滴加完毕。0℃下保温反应2小时。保温结束后升温至5℃左右。开始滴加甲基肼的四氢呋喃溶液(其中相对于1,5-二氮杂戊二烯盐，含有1.3当量的肼)，30min左右滴加完毕。慢慢升温至20℃，保温反应2小时。所得反应液60℃以下减压蒸馏回收四氢呋喃。尽量蒸干四氢呋喃。加入50-60℃热水500g。慢慢搅拌，降温至0℃，析出结晶。0℃左右析晶1-2小时。抽滤，水洗，抽干。干燥，得到产物155g，纯度HPLC 99.5％收率93.6％(以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率)。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧戊烷-2-基)-1H-吡唑。
Figure PCTCN2016085814-appb-000027
并且产物的元素分析和质谱分析结果如下：
质谱分析：m/z:218.09(100.0％),219.09(9.9％)。
元素分析：C,49.54；H,5.54；F,17.41；N,12.84；O,14.66。
向设置有搅拌装置和温度计的3000ml四口瓶中投入3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧戊烷-2-基)-1H-吡唑135g，水500g，30％盐酸180g(1.32mol)，升温至50-60℃，水解反应5h，滴加10％次氯酸钠溶液900g(1.21mol)，升温至100℃，回流反应5h，慢慢降温至10℃，析晶2h，抽滤，水洗，抽干。干燥，得到产物118g，纯度HPLC 99.3％收率91.8％(以化合物II计算摩尔收率)。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-二氟甲基-1-甲基-1H-吡唑-4-甲酸。
实施例7：3-二氟甲基-1-乙基-1H-吡唑-4-甲酸的合成
Figure PCTCN2016085814-appb-000028
除了用乙基肼的四氢呋喃溶液代替甲基肼的四氢呋喃溶液之外，重复实施例6制备3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧戊烷-2-基)-1H-吡唑的过程，并且以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率，收率为90.9％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-乙基-4-(2-甲基-1,3-二氧戊烷-2-基)-1H-吡唑。结构式如下所示：
Figure PCTCN2016085814-appb-000029
3-(二氟甲基)-1-乙基-4-(2-甲基-1,3-二氧戊烷-2-基)-1H-吡唑的元素分析和质谱分析结果如下：
质谱分析：m/z:232.10(100.0％),233.11(11.1％)。
元素分析：C,51.72；H,6.08；F,16.36；N,12.06；O,13.78。
以3-(二氟甲基)-1-乙基-4-(2-甲基-1,3-二氧戊烷-2-基)-1H-吡唑为中间体，重复实施例6中制备3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的过程，以3-(二氟甲基)-1-乙基-4-(2-甲基-1,3-二氧戊烷-2-基)-1H-吡唑为基准，计算摩尔收率，收率为91.5％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-二氟甲基-1-乙基-1H-吡唑-4-甲酸。最终产物的元素分析和质谱分析结果如下：
质谱分析：m/z:190.06(100.0％),191.06(7.7％)。
元素分析：C,44.22；H,4.24；F,19.98；N,14.73；O,16.83。
实施例8：3-二氟甲基-1-乙基-1H-吡唑-4-甲酸的合成
Figure PCTCN2016085814-appb-000030
除了用乙基肼的四氢呋喃溶液代替甲基肼的四氢呋喃溶液之外，重复实施例5制备3-(二氟甲基)-1-甲基-4-(1,3-二氧戊烷-2-基)-1H-吡唑的过程，并且以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率，收率为90.6％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-乙基-4-(1,3-二氧戊烷-2-基)-1H-吡唑。结构式如下所示：
Figure PCTCN2016085814-appb-000031
3-(二氟甲基)-1-乙基-4-(1,3-二氧戊烷-2-基)-1H-吡唑的元素分析和质谱分析结果如下：
质谱分析：m/z:218.09(100.0％),219.09(9.9％)。
元素分析：C,49.54；H,5.54；F,17.41；N,12.84；O,14.66。
以3-(二氟甲基)-1-乙基-4-(1,3-二氧戊烷-2-基)-1H-吡唑为中间体，重复实施例5中制备3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的过程，以3-(二氟甲基)-1-乙基-4-(1,3-二氧戊烷-2-基)-1H-吡唑基准，计算摩尔收率，收率为91.2％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-二氟甲基-1-乙基-1H-吡唑-4-甲酸。
实施例9：3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的合成
Figure PCTCN2016085814-appb-000032
若n＝0,R4＝甲基，则(IV)为
Figure PCTCN2016085814-appb-000033
即N,N-二甲胺基丙烯酮。
向设置有搅拌装置和温度计的1000ml四口瓶中投入N-1,1,2,2-四氟乙基二甲基胺73g(0.5mol)和乙腈300g，然后在20℃滴加BF3乙腈溶液160g(其中相对于使用的N-1,1,2,2-四氟乙基二甲基胺，含有1.2当量的BF3)，滴加时间为15-30min，搅拌30min。滴加N,N-二甲基胺基丙烯酮73.5g(0.65mol)，30min滴加完毕。20℃下保温反应2小时。保温结束后降温至5℃左右，滴加甲基肼的乙腈溶液(其中相对于1,5-二氮杂戊二烯盐，含有1.2当量的肼)，30min左右滴加完毕。慢慢升温至20℃，保温反应2小时。所得反应液60℃以下减压蒸馏回收乙腈。加入50-60℃热水250g。慢慢搅拌，降温至0℃，析出结晶，析晶时间为1-2小时。抽滤，水洗，抽干。干燥，得到产物72g，纯度HPLC 99.3％，收率90.3％(以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率)。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-甲基-1H-吡唑-4-乙酮。
Figure PCTCN2016085814-appb-000034
3-(二氟甲基)-1-甲基-1H-吡唑-4-乙酮的元素分析和质谱分析结果如下：
质谱分析：m/z:174.06(100.0％),175.06(8.3％)。
元素分析：C,48.28；H,4.63；F,21.82；N,16.09；O,9.19。
向设置有搅拌装置和温度计的2000ml四口瓶中投入前述化合物(II)72g，滴加10％次氯酸钠溶液500g(0.67mol)，升温至100℃，回流反应5h，慢慢降温至10℃，析晶2h，抽滤，水洗，抽干。干燥，得到产物56g，纯度HPLC 99.5％，收率91.3％(以化合物II计算摩尔收率)。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-二氟甲基-1-甲基-1H-吡唑-4-甲酸。
实施例10：3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的合成
Figure PCTCN2016085814-appb-000035
若n＝0,R4＝氢，则(IV)为
Figure PCTCN2016085814-appb-000036
即N,N-二甲胺基丙烯醛
向设置有搅拌装置和温度计的2000ml四口瓶中投入N-1,1,2,2-四氟乙基二甲基胺145g(1.0mol)和乙腈700g，然后在20℃滴加BF3乙腈溶液1650g(其中相对于使用的N-1,1,2,2-四氟乙基二甲基胺，含有1.3当量的BF3)，滴加时间为15-30min，搅拌30min。滴加N,N-二甲基胺基丙烯醛120g(1.10mol)，30min滴加完毕。20℃下保温反应2小时。保温结束后降温至5℃左右，滴加甲基肼的乙腈溶液(其中相对于1,5-二氮杂戊二烯盐，含有1当量的肼)，30min左右滴加完毕。慢慢升温至20℃，保温反应2小时。所得反应液60℃以下减压蒸馏回收乙腈。加入50-60℃热水600g。慢慢搅拌，降温至0℃，析出结晶，析晶时间为1-2小时。抽滤，水洗，抽干。干燥，得到产物148g，纯度HPLC 99.3％，收率92.8％(以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率)。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-甲基-1H-吡唑-4-甲醛。
Figure PCTCN2016085814-appb-000037
3-(二氟甲基)-1-甲基-1H-吡唑-4-乙醛的元素分析和质谱分析结果如下：
质谱分析：m/z:160.04(100.0％),161.05(8.3％)。
元素分析：C,45.01；H,3.78；F,23.73；N,17.50；O,9.99。
向设置有搅拌装置和温度计的3000ml四口瓶中投入前述化合物(II)148g，滴加10％次氯酸钠溶液1000g(1.34mol)，升温至100℃，回流反应5h，慢慢降温至10℃，析晶2h，抽滤， 水洗，抽干。干燥，得到产物115g，纯度HPLC 99.5％收率91.3％(以化合物II计算摩尔收率)。。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-二氟甲基-1-甲基-1H-吡唑-4-甲酸。
实施例11：3-二氟甲基-1-乙基-1H-吡唑-4-甲酸的合成
除了用乙基肼的乙腈溶液代替甲基肼的乙腈溶液之外，重复实施例9中制备3-(二氟甲基)-1-甲基-1H-吡唑-4-乙酮的过程，并且以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率，收率为91.4％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-乙基-1H-吡唑-4-乙酮。
Figure PCTCN2016085814-appb-000038
3-(二氟甲基)-1-乙基-1H-吡唑-4-乙酮的元素分析和质谱分析结果如下：
质谱分析：m/z:188.08(100.0％),189.08(8.8％)。
元素分析：C,51.06；H,5.36；F,20.19；N,14.89；O,8.50。
以3-(二氟甲基)-1-乙基-1H-吡唑-4-乙酮为中间体，重复实施例9中制备3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的过程，以3-(二氟甲基)-1-乙基-1H-吡唑-4-乙酮为基准，计算摩尔收率，收率为91.5％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-二氟甲基-1-乙基-1H-吡唑-4-甲酸。
实施例12：3-二氟甲基-1-乙基-1H-吡唑-4-甲酸的合成
除了用乙基肼的乙腈溶液代替甲基肼的乙腈溶液之外，重复实施例10制备3-(二氟甲基)-1-甲基-1H-吡唑-4-乙醛的过程，并且以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率，收率为92.4％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-乙基-1H-吡唑-4-甲醛。
Figure PCTCN2016085814-appb-000039
3-(二氟甲基)-1-乙基-1H-吡唑-4-乙醛的元素分析和质谱分析结果如下：
质谱分析：m/z:1674.06(100.0％),175.06(8.3％)。
元素分析：C,48.28；H,4.63；F,21.82；N,16.09；O,9.19。
以3-(二氟甲基)-1-乙基-1H-吡唑-4-乙醛为中间体，重复实施例10中制备3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的过程，以3-(二氟甲基)-1-乙基-1H-吡唑-4-乙醛为基准，计算摩尔收率，收率为94.1％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3- 二氟甲基-1-乙基-1H-吡唑-4-甲酸。
实施例13：3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的合成
除了使用N,N-二甲基-2-(2-甲基-1,3-二氧己烷-2-基)-乙烯代替N,N-二甲基-2-(2-甲基-1,3-二氧丁烷-2-基)-乙烯之外，重复实施例2制备3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧丁烷-2-基)-1H-吡唑的过程，并且以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率，收率为91.9％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧己烷-2-基)-1H-吡唑。结构式如下所示：
Figure PCTCN2016085814-appb-000040
3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧己烷-2-基)-1H-吡唑的元素分析和质谱分析结果如下：
质谱分析：m/z:232.10(100.0％),233.11(11.1％)。
元素分析：C,51.72；H,6.08；F,16.36；N,12.06；O,13.78。
以3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧己烷-2-基)-1H-吡唑为中间体，重复实施例2中制备3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的过程，以3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧己烷-2-基)-1H-吡唑为基准，计算摩尔收率，收率为92.3％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-二氟甲基-1-甲基-1H-吡唑-4-甲酸。
实施例14：3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的合成
除了使用N,N-二甲基-2-(1,3-二氧己烷-2-基)-乙烯代替N,N-二甲基-2-(1,3-二氧戊烷-2-基)-乙烯之外，重复实施例5制备3-(二氟甲基)-1-甲基-4-(1,3-二氧戊烷-2-基)-1H-吡唑的过程，并且以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率，收率为90.9％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-甲基-4-(1,3-二氧己烷-2-基)-1H-吡唑。结构式如下所示：
Figure PCTCN2016085814-appb-000041
3-(二氟甲基)-1-甲基-4-(1,3-二氧己烷-2-基)-1H-吡唑的元素分析和质谱分析结果如下：
质谱分析：m/z:218.09(100.0％),219.09(9.9％)。
元素分析：C,49.54；H,5.54；F,17.41；N,12.84；O,14.66。
以3-(二氟甲基)-1-甲基-4-(1,3-二氧己烷-2-基)-1H-吡唑为中间体，重复实施例5中制备3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的过程，3-(二氟甲基)-1-甲基-4-(1,3-二氧己烷-2-基)-1H-吡唑 为基准，计算摩尔收率，收率为91.6％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-二氟甲基-1-甲基-1H-吡唑-4-甲酸。
实施例15：3-二氟甲基-1-乙基-1H-吡唑-4-甲酸的合成
除了使用N,N-二甲基-2-(2-甲基-1,3-二氧己烷-2-基)-乙烯代替N,N-二甲基-2-(2-甲基-1,3-二氧丁烷-2-基)-乙烯，并且使用除了用乙基肼的四氢呋喃溶液代替甲基肼的乙腈溶液之外，重复实施例2制备3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧丁烷-2-基)-1H-吡唑的过程，并且以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率，收率为91.6％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-乙基-4-(2-甲基-1,3-二氧己烷-2-基)-1H-吡唑。结构式如下所示：
Figure PCTCN2016085814-appb-000042
3-(二氟甲基)-1-乙基-4-(2-甲基-1,3-二氧己烷-2-基)-1H-吡唑的元素分析和质谱分析结果如下：
质谱分析：m/z:246.12(100.0％),247.12(12.9％),248.12(1.1％)。
元素分析：C,53.65；H,6.55；F,15.43；N,11.38；O,12.99。
以3-(二氟甲基)-1-乙基-4-(2-甲基-1,3-二氧己烷-2-基)-1H-吡唑为中间体，重复实施例2中制备3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的过程，以3-(二氟甲基)-1-乙基-4-(2-甲基-1,3-二氧己烷-2-基)-1H-吡唑为基准，计算摩尔收率，收率为92.2％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-二氟甲基-1-乙基-1H-吡唑-4-甲酸。
实施例16：3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的合成
除了使用N,N-二甲基-2-(2-甲基-1,3-二氧庚烷-2-基)-乙烯代替N,N-二甲基-2-(2-甲基-1,3-二氧丁烷-2-基)-乙烯之外，重复实施例2制备3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧丁烷-2-基)-1H-吡唑的过程，并且以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率，收率为91.1％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧庚烷-2-基)-1H-吡唑。结构式如下所示：
Figure PCTCN2016085814-appb-000043
3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧庚烷-2-基)-1H-吡唑的元素分析和质谱分析结果如下：
质谱分析：m/z:246.12(100.0％),247.12(12.9％),248.12(1.1％)。
元素分析：C,53.65；H,6.55；F,15.43；N,11.38；O,12.99。
以3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧庚烷-2-基)-1H-吡唑为中间体，重复实施例2中制备3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的过程，以3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧庚烷-2-基)-1H-吡唑为基准，计算摩尔收率，收率为92.0％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-二氟甲基-1-甲基-1H-吡唑-4-甲酸。
实施例17：3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的合成
除了使用N,N-二甲基-2-(1,3-二氧庚烷-2-基)-乙烯代替N,N-二甲基-2-(1,3-二氧戊烷-2-基)-乙烯之外，重复实施例5制备3-(二氟甲基)-1-甲基-4-(1,3-二氧戊烷-2-基)-1H-吡唑的过程，并且以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率，收率为90.8％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-甲基-4-(1,3-二氧庚烷-2-基)-1H-吡唑。结构式如下所示：
Figure PCTCN2016085814-appb-000044
3-(二氟甲基)-1-甲基-4-(1,3-二氧庚烷-2-基)-1H-吡唑的元素分析和质谱分析结果如下：
质谱分析：m/z:232.10(100.0％),233.11(11.1％)。
元素分析：C,51.72；H,6.08；F,16.36；N,12.06；O,13.78。
以3-(二氟甲基)-1-甲基-4-(1,3-二氧庚烷-2-基)-1H-吡唑为中间体，重复实施例5中制备3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的过程，3-(二氟甲基)-1-甲基-4-(1,3-二氧庚烷-2-基)-1H-吡唑为基准，计算摩尔收率，收率为91.5％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-二氟甲基-1-甲基-1H-吡唑-4-甲酸。
实施例18：3-二氟甲基-1-乙基-1H-吡唑-4-甲酸的合成
除了使用N,N-二甲基-2-(2-甲基-1,3-二氧庚烷-2-基)-乙烯代替N,N-二甲基-2-(2-甲基-1,3-二氧丁烷-2-基)-乙烯，并且使用除了用乙基肼的四氢呋喃溶液代替甲基肼的乙腈溶液之外，重复实施例2制备3-(二氟甲基)-1-甲基-4-(2-甲基-1,3-二氧丁烷-2-基)-1H-吡唑的过程，并且以N-1,1,2,2-四氟乙基二甲基胺计算摩尔收率，收率为91.7％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-(二氟甲基)-1-乙基-4-(2-甲基-1,3-二氧庚烷-2-基)-1H-吡唑。结构式如下所示：
Figure PCTCN2016085814-appb-000045
3-(二氟甲基)-1-乙基-4-(2-甲基-1,3-二氧庚烷-2-基)-1H-吡唑的元素分析和质谱分析结果如下：
质谱分析：m/z:260.13(100.0％),261.14(13.3％),262.14(1.2％)。
元素分析：C,55.37；H,6.97；F,14.60；N,10.76；O,12.29。
以3-(二氟甲基)-1-乙基-4-(2-甲基-1,3-二氧庚烷-2-基)-1H-吡唑为中间体，重复实施例2中制备3-二氟甲基-1-甲基-1H-吡唑-4-甲酸的过程，以3-(二氟甲基)-1-乙基-4-(2-甲基-1,3-二氧庚烷-2-基)-1H-吡唑为基准，计算摩尔收率，收率为92.1％。所得产物进行1H NMR分析、元素分析和质谱分析，可以确定所得产品为3-二氟甲基-1-乙基-1H-吡唑-4-甲酸。

Claims (15)

  1. 一种式(II)化合物，
    Figure PCTCN2016085814-appb-100001
    其中
    R1选自甲基或乙基，优选甲基；
    R4为氢或甲基，优选甲基；
    n为0-4，优选0或1；
    X为F、Cl或CF3，优选F。
  2. 根据权利要求1所述的化合物，其中R1为甲基，R4为甲基，n为1，X为F。
  3. 根据权利要求1所述的化合物，其中R1为甲基，R4为甲基，n为0，X为F。
  4. 根据权利要求1所述的化合物，其中R1为乙基，R4为甲基，n为0，X为F。
  5. 式(II)化合物的制备方法，所述方法包括以下步骤：
    (1)在路易斯酸的存在下，将式(III)的α-氟胺与式(IV)的乙烯衍生物反应，生成式(V)的vinamidinium盐(即1,5-二氮杂戊二烯盐)，
    式(III)的α-氟胺如下所示：
    Figure PCTCN2016085814-appb-100002
    其中X的定义如前所述，R2和R3独立地选自C1-C4烷基，优选甲基；
    式(IV)的乙烯衍生物如下所示：
    Figure PCTCN2016085814-appb-100003
    其中R4为氢或甲基，优选甲基，n为0-4，优选0或1；
    并且其中当n＝0时，式(IV)的乙烯衍生物如下所示：
    Figure PCTCN2016085814-appb-100004
    Figure PCTCN2016085814-appb-100005
    式(V)的1,5-二氮杂戊二烯盐如下所示：
    Figure PCTCN2016085814-appb-100006
    其中n、R2和R3、R4的定义如前所述，Y-为阴离子，所述阴离子选自[BF4]-、[AlCl3F]-、[AlF4]-、[ZnCl2F]-、[SbF6]-、[SnCl4F]-、[BiCl3F]-、[GaCl3F]-和[SiCl4F]-，其来自相应的路易斯酸；
    并且其中当n＝0时，式(V)的1,5-二氮杂戊二烯盐如下所示：
    Figure PCTCN2016085814-appb-100007
    (2)式(V)的1,5-二氮杂戊二烯盐与肼反应，得到式(II)的化合物。
  6. 一种式(I)化合物的制备方法
    Figure PCTCN2016085814-appb-100008
    其中R1选自甲基或乙基，优选甲基；
    X为F、Cl或CF3，优选F，
    所述方法包括以下步骤：
    (1)在路易斯酸的存在下，将式(III)的α-氟胺与式(IV)的乙烯衍生物反应，生成式(V)的vinamidinium盐(即1,5-二氮杂戊二烯盐)，
    式(III)的α-氟胺如下所示：
    Figure PCTCN2016085814-appb-100009
    其中X的定义如前所述，R2和R3独立地选自C1-C4烷基，优选甲基；
    式(IV)的乙烯衍生物如下所示：
    Figure PCTCN2016085814-appb-100010
    其中R4为氢或甲基，优选甲基，n为0-4，优选0或1；
    并且其中当n＝0时，式(IV)的乙烯衍生物如下所示：
    Figure PCTCN2016085814-appb-100011
    式(V)的1,5-二氮杂戊二烯盐如下所示：
    Figure PCTCN2016085814-appb-100012
    其中n、R2和R3、R4的定义如前所述，Y-为阴离子，所述阴离子选自[BF4]-、[AlCl3F]-、[AlF4]-、[ZnCl2F]-、[SbF6]-、[SnCl4F]-、[BiCl3F]-、[GaCl3F]-和[SiCl4F]-；
    并且其中当n＝0时，式(V)的1,5-二氮杂戊二烯盐如下所示：
    Figure PCTCN2016085814-appb-100013
    (2)式(V)的1,5-二氮杂戊二烯盐与肼反应，得到式(II)的化合物，
    式(II)的化合物如下所示：
    Figure PCTCN2016085814-appb-100014
    其中X、n、R1和R4的定义如前所述；
    并且其中，n＝0时，式(II)化合物结构如下所示：
    Figure PCTCN2016085814-appb-100015
    (3)n＝1-4的式(II)的化合物经过水解和氧化，或者n＝0的式(II)的化合物经过氧化，得到式(I)的化合物。
  7. 根据权利要求5或6所述的方法，其特征在于步骤(1)中路易斯酸选自BF3、AlCl3、AlF3、ZnCl2、PF5、SbF5、SnCl4、BiCl3、GaCl3、SiCl4的化合物，优选BF3；路易斯酸与α-氟胺的摩尔比在1:1至10:1之间，优选1:1至5:1，更优选1:1至1.3:1之间。
  8. 根据权利要求5或6所述的方法，其特征在于步骤(1)和(2)中反应温度为-20℃至60℃，优选-10℃至40℃，更优选0℃-30℃。
  9. 根据权利要求5或6所述的方法，其特征在于步骤(2)在溶剂的存在下反应，其中 溶剂选自乙醚、乙腈、二氯甲烷和四氢呋喃，优选乙腈或四氢呋喃。
  10. 根据权利要求5或6所述的方法，其特征在于步骤(2)中使用的肼为甲基肼或乙基肼，优选甲基肼。
  11. 根据权利要求5或6所述的方法，其特征在于步骤(2)中式(V)的1,5-二氮杂戊二烯盐与肼的摩尔比在1:10至10:1之间，优选1:5至5:1之间，更优选1.3:1至1:1.3之间。
  12. 根据权利要求5或6所述的方法，其特征在于步骤(3)中式(II)化合物的水解反应在溶剂的存在下进行，所述溶剂选自甲醇、乙醇、乙腈、四氢呋喃等与水的混合液，或使用单一的水作为溶剂，优选使用水或四氢呋喃作溶剂。
  13. 根据权利要求5或6所述的方法，其特征在于步骤(3)中水解反应在酸性条件下进行，所用的酸为为盐酸，硫酸，氢溴酸，磷酸等，优选盐酸或硫酸，式(II)化合物与酸的摩尔比在1:2至1:10之间，优选1:3至1:5之间，更优选1:2至1:3之间。
  14. 根据权利要求5或6所述的方法，其特征在于步骤(3)中所用的氧化剂选自双氧水、次氯酸钠、高锰酸钾、氯酸钠或氯酸钾等，优选双氧水或次氯酸钠，氧化反应温度为30℃至100℃，优选50℃至100℃，更优选70℃100℃。
  15. 根据权利要求5或6所述的方法，其特征在于步骤(3)中水解反应和氧化反应连续进行，式(II)化合物与氧化剂的摩尔比在1:2至1:10之间，优选1:3至1:5之间，更优选1:2至1:3之间。
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