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CAS No. :141573-96-8 MDL No. :
Formula : C6H5ClF2N2O Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 194.57 Pubchem ID :-
Synonyms :

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  • Downstream synthetic route of [ 141573-96-8 ]

[ 141573-96-8 ] Synthesis Path-Downstream   1~23

  • 1
  • [ 141573-96-8 ]
  • [ 960053-41-2 ]
  • 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [2-(2,4-dichlorophenyl)-2-fluoro-ethyl]-amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% With triethylamine In dichloromethane at 20℃; for 2h; P3 Example P3: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid r2-(2.4-dichlorophenyl)-2-fluoro-ethyll-amide (compound no. 1.206):A solution of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carbonyl chloride (0.148g; 0.758 mmol) in dichloromethane (3ml) was added dropwise to a stirred solution of 0.15Og (0.721 mmol) 2-(2,4-dichloro-phenyl)-2-fluoro-propylamine hydrochloride (compound Z1.206), which was prepared as described in example P10, and triethylamine (301 μl; 2.16 mmol) in dichloromethane (12ml). The reaction mixture was stirred for 2hr at ambient temperature then washed with 1 M NaOH (10ml), 1 M HCI (10ml), water (10 ml) and then dried over Na2SO4. 190mg (72% of theory) of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid [2-(2,4-dichlorophenyl)-2-fluoro-ethyl]-amide (compound no. 1.206) was obained in form of a resin. 1H NMR (400MHz, CDCI3): δ 3.62-3.75 and 3.92-4.15(m, 2H1CH2), 3.87(s,3H,NCH3), 5.86- 5.89 and 5.98-6.01(m,1 H,CH), 6.67(t,1 H1NH), 6.82(t,1 H1CHF2), 7.29(d,1 H1Ar-H)1 7.37(d,1 H1Ar-H), 7.41 (d,1 H1Ar-H), 7.91(s,1 H,pyrazole-H). MS [M+H]+ 366/368/370.
  • 2
  • [ 176969-34-9 ]
  • [ 141573-96-8 ]
YieldReaction ConditionsOperation in experiment
98% With thionyl chloride; In chlorobenzene; at 110℃; for 3h; Example A2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carbonyl chloride:; 69.5 g of thionyl chloride (0.58 mol, 1.17 equivalents) are added at 1100C in the course of 2 hours to a solution of 88 g of 3-difluoromethyl-1 -methyl-1 H-pyrazole-4-carboxylic acid (0.5 mol) in 440 g of chlorobenzene. The reaction mixture is stirred for 1 hour at 1 100C. The reaction mixture is concentrated to a crude product solution. 190 g of 3-difluoromethyl-1- methyl-1 H-pyrazole-4-carbonyl chloride (50% in chlorobenzene, yield: 98%) is obtained. The crude product solution is used without being further purified.
92.1% With thionyl chloride; In toluene; at 90℃; A solution of 293 g of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid, prepared analogously to example 2, in 700 g of toluene was heated at 90 C., and 260 g of thionyl chloride were added over a period of 3.5 h. The mixture was allowed to cool and concentrated under reduced pressure, 100 ml of toluene were added to the residue and the mixture was again concentrated under reduced pressure. The residue was distilled over a packed column at a pressure of 0.8 mbar and a head temperature of 109 C., which gave 298.4 g of the acid chloride of a purity of 99% (yield 92.1%).
90% With thionyl chloride; N,N-dimethyl-formamide; In 1,2-dichloro-ethane; for 5h;Reflux; At room temperature, 3-(difluoromethyl)-1-methyl-1hydro-pyrazole-4-carboxylic acid (1.76g, 0.01mol), dichloroethane (20ml) and N, N-dimethyl Carboxamide (0.05g) was added to a three-necked flask, and dichlorosulfoxide (2.02g, 0.02mol) was added dropwise to the above mixture. Heat to reflux for 5 hours. The heating was stopped and the solvent and residual dichlorosulfoxide were removed under reduced pressure to obtain 1.75 g of product with a yield of 90%.
78.25% With thionyl chloride; for 2h;Reflux; To a one-necked flask was added 53.00 g <strong>[176969-34-9]3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid</strong> and 72 mL of thionyl chloride,Heating up to the system has a reflow phenomenon,After refluxing for 2 h, the unreacted thionyl chloride was evaporated at atmospheric pressure.System cooling to 60 below, an external anhydrous calcium chloride drying tower,Water pump vacuum distillation of low boiling impurities, get red viscous liquid, placed overnight solidified into white crystals.The yield was 78.25%.
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h; PREPARATION EXAMPLES Preparation of compound No. 3 At room temperature, 70 mul (0.8 mmol) of oxal chloride and 30 mul of dimethylformamide are added to a suspension consisting of 130.0 mg (0.7 mmol) of <strong>[176969-34-9]3-(difluoromethyl)-1-methyl-1H-pyrazol-4-carboxylic acid</strong> in 5 ml of dichloromethane. After 2 hours, this reaction mixture is added dropwise to a solution consisting of 160.0 mg (0.7 mmol) of N-cyclopropyl-2-(1,3-dimethylbutyl)aniline and 130 mul (1.0 mmol) of triethylamine in 5 ml of dichloromethane. After 48 hours of stirring at room temperature, 4 ml of water are added and the organic phase is separated off, dried over magnesium sulphate and concentrated under reduced pressure. This gives, after column chromatography (gradient cyclohexane/ethyl acetate), 202.0 mg (0.5 mmol, 72% of theory) of N-cyclopropyl-3-(difluoromethyl)-N-[2-(1,3-dimethylbutyl)phenyl]-1-methyl-1H-pyrazol-4-carboxamide [log P (pH 2.3) 3.89].
With dmap; thionyl chloride; In 1,2-dichloro-ethane; for 2h;Reflux; To a solution of 600 mg of 3-difluoromethyl-1- methyl-lH-pyrazole-4-carboxylic acid [compound (III)] and a catalytic amount of N, -dimethylformamide in dichloromethane (7 mL) , 450 mg of thionyl chloride were added dropwise. The mixture was refluxed for 2h. The reaction was monitored by GC/MS . The solvent was evaporated in vacuo. The crude acid chloride obtained was used in the following step.
With thionyl chloride; for 1h;Reflux; A mixture of 3-(difiuoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid (0.25 g, 1.42 mmol) and thionyl chloride (5 mL) was heated to reflux for 1 h. The cooled reaction mixture was concentrated under reduced pressure and the resulting residue was twice diluted with toluene and concentrated under reduced pressure. The residual 3 -(difiuoromethyl)- 1-methyl- lH-pyrazole-4-carbonyl chloride was taken up in dichloromethane (5 mL) and treated dropwise at room temperature with a mixture of 6-chloro-N-cyclopropyl-a-methyl-3- pyridinemethanamine (i.e. the product of Step A, 0.23 g, 1.18 mmol) and triethylamine (0.12 g, 1.18 mmol) in dichloromethane. The reaction mixture was stirred overnight at ambient temperature, and then partitioned between IN hydrochloric acid and dichloromethane. The organic phase was separated and the aqueous phase extracted again with dichloromethane. The combined organic phases were dried (MgSC^) and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 30 to 100% ethyl acetate in hexanes to yield the title compound (0.27 g). in NMR delta 8.39 (m, 1H), 7.65 (m, 2H), 7.28 (d, 1H), 7.01 (t, 1H), 5.68 (m, 1H), 3.96 (s, 3H), 2.62 (m, 1H), 1.79 (d, 3H), 0.64 (m, 2H), 0.52 (m, 1H), 0.35 (m, 1H).
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h; To 176 mg of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid in 1 ml of dichloromethane, 10 mg of N,N-dimethylformamide and 381 mg of oxalyl chloride were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in 2 ml of dichloromethane, and to the solution, 190 mg of the 2-amino-1-(3,5-dichloropyridin-2-yl)ethanone-O-ethyloxime prepared in Step 5 in Synthetic Example 2 in 2 ml of dichloromethane and then 91 mg of pyridine were added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 2 hours. After completion of the reaction, the reaction mixture was mixed with 10 ml of water and extracted with chloroform (20 ml*1), the resulting organic layer was washed with water (10 ml*1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:4 to 1:1) as the eluent to obtain 165.3 mg of a pale yellow resinous substance. The resinous substance was dissolved in 5 ml of acetic acid and stirred at 70C for 2 hours, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:4 to 1:1) as the eluent to obtain 130.6 mg of the desired product as a colorless resinous substance (E/Z=1/1). 1H NMR (CDCl3, Me4Si, 300MHz) delta8.50 and 8.47 (d, J=2.1 Hz, 1 H), 7.90 and 7.86 (s, 1H), 7.76 and 7.75 (d, J=2.1Hz, 1H), 6.9-7.1 (m, 1H), 6.84 and 6.73 (t, J=54.3Hz, 1H), 4.71 and 4.49 (d, J=6.0Hz, 2H), 4.31 and 4.14 (q, J=7.2Hz, 2H), 3.92 and 3.89 (s, 3H), 1.36 and 1.23 (t, J=7.2Hz, 3H).
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; for 2h;Reflux; To a solution of 600 mg of <strong>[176969-34-9]3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid</strong> [compound (III)] and a catalytic amount of N,N-dimethylformamide in dichloromethane (7 mL), 450 mg of thionyl chloride were added dropwise. The mixture was refluxed for 2 h. The reaction was monitored by GC/MS. The solvent was evaporated in vacuo. The crude acid chloride obtained was used in the following step.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h; N dichloromethane 1ml solution of 3-difluoromethyl-1-methyl -1H- pyrazole-4-carboxylic acid 176mg, added N- dimethylformamide 10mg and oxalyl chloride 381mg, I was stirred at room temperature for 1 hour.After completion of the reaction, distilling off the solvent under reduced pressure, the residue was dissolved in dichloromethane 2ml, 2- amino-1- (3,5-dichloropyridine prepared with stirring under ice-cooling, at step 5 Synthesis Example 2 2-yl) ethanone -O- dichloromethane 2ml solution of ethyl oxime 190mg, then dropped the pyridine 91mg, was continued for a further 2 hours stirring at room temperature after completion of the dropping.After completion of the reaction, and extracted with added water 10ml reaction mixture chloroform (20mlx1), after the organic layer washed with water (10mlx1), and dehydrated and dried in this order brine then anhydrous sodium sulfate, and distilling off the solvent under reduced pressure It was.The residue was ethyl acetate - hexane (1: 4 to 1: 1 gradient) was purified by silica gel column chromatography eluting with, to give a pale yellow resinous substance 165.3mg.The thing is dissolved in acetic acid 5ml, After stirring for 2 hours at 70 , distilling off the solvent under reduced pressure, the residue partitioned between ethyl acetate - hexane (1: 4 to 1: 1 gradient) and eluting with It was purified by silica gel column chromatography, and the desired compound 130.6mg obtained as a colorless resin-like substance (E / Z = 1/1).
With thionyl chloride; for 4h;Reflux; To a solution of SOCl2 (5.35 g, 30 mmol), the <strong>[176969-34-9]3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid</strong> 3 (1.32 g, 7.50 mmol) was added dropwisely. Then the mixture was refluxed for 4 h. After the reaction is completed, the excess of SOCl2 was evaporated to give 4 as a yellow liquid that was used without further purification [39] . 1H NMR (400 MHz, CDCl3), delta 4.00 (s, 3H, N-CH3), 6.90 (t, J = 54.2 Hz, 1H, -CHF2), 8.09 (s, 1H, pyrazolyl-H).
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h; 335 mg of oxalyl chloride and 5 mg of N, N-dimethylformamide were added to a solution of 256 mg of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid in 3 ml of dichloromethane, And the mixture was stirred for 2 hours.Then, the solvent was distilled off under reduced pressure, and the residue was dissolved in 3 ml of tetrahydrofuran.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h; Step 7: Production of N-[2-[3-chloro-5-(cyclopropylethynyl)pyridin-2-yl]-2-(isopropoxyimino)ethyl]-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxamide To a 1 ml solution of 68 mg of <strong>[176969-34-9]3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid</strong> in dichloromethane, 10 mg of N,N-dimethylformamide and 66 mg of oxalyl chloride were added. After completion of the addition, the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure. The obtained residue was dissolved in 1 ml of dichloromethane and, with stirring under cooling with ice, added dropwisely to a mixed solution of 100 mg of 2-amino-1-[3-chloro-5-(cyclopropylethynyl)pyridin-2-yl]ethanone-O-isopropyl oxime and 200 mg of potassium carbonate in 2 ml of dichloromethane and 2 ml of water. After completion of the dropwise addition, stirring was further continued for 1 hour at room temperature. After completion of the reaction, 10 ml of water was added to the reaction mixture, followed by extraction with dichloromethane (10 ml*1). The obtained organic layer was washed with water (10 ml*1), and then dehydrated and dried by using saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography by eluting it with ethyl acetate-hexane (2:3), to obtain 150 mg of the desired product as a pale yellow resinous substance (E/Z=2/1). 1H NMR (CDCl3, Me4Si, 300 MHz) b 8.45 and 8.43 (d, J=1.8 Hz, 1H), 7.88 and 7.82 (s, 1H), 7.68 and 7.66 (d, J=1.8 Hz, 1H), 7.12 (bs, 1H), 6.85 and 6.75 (t, J=54.2 Hz, 1H), 4.70 and 4.46 (d, J=6.1, 4.9 Hz, 2H), 4.47 and 4.36 (sep, J=6.3 Hz, 1H), 3.90 and 3.87 (s, 3H), 1.4-1.55 (m, 1H), 1.32 and 1.18 (d, J=6.3 Hz, 6H), 0.8-1.0 (m, 4H).
With thionyl chloride; at 90℃; for 3h; The main procedure is shown in Scheme 2. The raw products of compound 7 were synthesized via one-pot method in a flask containing compounds 5 (30 mmol), 6 (30 mmol), K2CO3 (15 mmol) and PEG1000 (0.45 mmol). The reactions were carried out under stirring at 185 C and were monitored by TLC. After reactions completion, the desired diphenylamine derivatives 7 were obtained via column chromatographic purification. Next, compounds 7 (20 mmol), reductive iron powder (60 mmol), solid NH4Cl (60 mmol) and ethanol aqueous solution (75%, 50 mL) were added. The reactions proceeded with refluxing for 3 h at 90 C and compounds 8 were obtained. Then, compound 3 (30 mmol) and SOCl2 (thionylchloride, 30 mL) were added. The mixture was heated to reflux at 90 C for 3 h. Residual SOCl2 was removed by vacuum distillation in order to obtain compound 4. Finally, the primary amines 8 (10 mmol) dissolved in dichloromethane (CH2Cl2, 5 mL) and triethylamine(Et3N, 10 mL) were added. The mixture was cooled to 0 C and compound 4 (20 mmol) dissolved in dichloromethane (CH2Cl2, 10 mL) was added dropwise under stirring at a temperature not exceeding 5 C. The final mixture was stirred at room temperature for 10 h and the target compounds 9a, 9b and 9c were purified via column chromatography and recrystallization.
With thionyl chloride; In 5,5-dimethyl-1,3-cyclohexadiene; at 100℃; for 20h;Inert atmosphere; <Step (G)> At room temperature under a nitrogen atmosphere, 14.0 parts of 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid and 35.1 parts of xylene were mixed. The obtained mixture was heated at 100 C. To the obtained mixture was added dropwise 11.2 parts of thionyl chloride over 5 hours. The obtained mixture was stirred at 100 C. for 15 hours and then cooled to 40 C. Thionyl chloride and xylene were evaporated from the obtained reaction mixture under reduced pressure to obtain brown 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid chloride.
With thionyl chloride; for 4h;Reflux; The compound of formula (III) was added to a 5% aqueous solution of sodium hydroxide, reacted at 60 C for 3 hours, and then hydrochloric acid was added to neutralize the pH to a weak acidity,(IV) <strong>[176969-34-9]1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid</strong>;The compound of formula (IV) (40 mmol) was refluxed with thionyl chloride (0.4 mol) for 4 hours and distilled under reduced pressure to give(V) 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride;
With thionyl chloride; for 4h;Reflux; The compound of formula (III) was added to a 5% aqueous solution of sodium hydroxide, reacted at 60 C for 3 hours, and then hydrochloric acid was added to neutralize the pH to a weak acidity,(IV) (40 mmol) was refluxed with thionyl chloride (0.4 mol) for 4 hours, and the compound of formula (IV)Methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride in the presence of 10 mL of methylene chloride was added to a solution of the compound of formula (V) Of ammonia(VI) 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxamide was obtained by distilling off the reaction at room temperature for 4 hours at the end of the reaction. (VII) was added to oxalyl chloride (0.1 mol), stirred at room temperature for 1 hour and refluxed for 5 hours. After completion of the reaction, the compound of formula (VII) was distilled off under reduced pressure.
Ca. 81 g With thionyl chloride; N,N-dimethyl-formamide; In n-heptane; at 42 - 45℃; for 2.5h; The pyrazole acid chloride is prepared from 3- difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid and thionyl chloride in heptane shortly before use. In a 500-mL round-bottomed flask provided with alkaline scrubber, pyrazole acid (74.0 grams, 0.42 mol) is suspended in heptane (170 mL) . Dimethylformamide (0.70 grams, 0.009 mol) and thionyl chloride (55.0 grams, 0.462 mol) are added and the bi-phasic mixture is stirred and heated at 42-45 C.After complete conversion of pyrazole acid (2.5 hours), the solvent and excess thionyl chloride are completely removed by vacuum distillation.Liquid pyrazole acid chloride is obtained as the residue (approximately 81.0 grams)
With thionyl chloride; for 4.5h;Reflux; <strong>[176969-34-9]1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid</strong> (7.76 g, 40 mmol) represented by formula (III) was refluxed with thionyl chloride (47.6 g, 0.4 mol) for 4 hours. When the reaction system turns to a pale yellow transparent liquid, the reaction is continued for 30 min. The reaction is stopped, and after cooling down to room temperature, 1-methyl-3-difluoromethyl-1H-pyrazole-4-acyl chloride is obtained by distillation under reduced pressure. 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride (2 mmol) was added to 15 ml of dichloromethane, Phenylmethanamine (2.1 mmol) was added followed by slow triethylamine (0.3 g, 3 mmol) stirring overnight at room temperature; followed by TLC (EA:PE=2:1 (V)) until the reaction was complete with dichloromethane. Three times extraction with water=1:1 (V) system, concentration of organic layer, extraction with toluene or 75% ethanol, and column chromatography (EA:PE=2:1(V)) to obtain N-benzyl as shown in (K11). 1-Methyl-3-(difluoromethyl)-1H-pyrazole-4-carboxamide
With thionyl chloride; at 80℃; for 3h;Reflux; Compound 2 (15 mmol) and SOCl2 (30 mL) were added. The mixtures were heated to reflux at 80 &176;C for 3 hours. Residual SOCl2 was removed by vacuum distillation in order to obtain compound 3. Finally, the compounds 6 (10 mmol) dissolved in dichloromethane (20 mL) and triethylamine (5 mL) were added. The mixtures were cooled to 0 &176;C and compound 3 dissolved in dichloromethane (20 mL) were added dropwise under stirring at a temperature not exceeding 5 &176;C. The final mixtures were stirred at room temperature for 3 hours and the target compounds 1a-1p were purified via column chromatography.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0℃;Inert atmosphere; a synthesis reaction experimental device is connected in a circulating cooling reaction pump at 0 C, and nitrogen gas is introduced in the early stage.To remove the air from the reaction flask, keep nitrogen in, and add <strong>[176969-34-9]1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid</strong> to the round bottom flask after about 5 minutes.(LM-1-a) 0.528 g (3 mmol), 20 mL of re-distilled dichloromethane,Re-steaming DMF 0.482 mL (6 mmol),The reaction liquid was stirred and 0.316 mL (3.6 mmol) of oxalyl chloride was slowly added dropwise thereto using a dropping funnel. After 1.5h-2.5h reactionThe reaction was closed, and the insoluble material was removed by suction under reduced pressure. The filtrate was slowly added dropwise to a solution of 0.856 g (2.4 mmol) of N-(2-fluorophenyl)-2-aminocyclohexanesulfonamide and 0.6 mL with a dropping funnel. 4.32mmol) triethylamine in a mixed solution of dichloromethane, continue to be lowAfter stirring for 15 min, the reaction was changed to room temperature for about 2 h, and the reaction was monitored by TLC [V (petroleum ether): V (ethyl acetate) = 2:1].During the reaction, the reaction of the raw materials is judged according to the condition of the plate. After the reaction is completed, the reaction is stopped. AdditionalAppropriate amount of methylene chloride, the reaction solution was washed with HCl, washed with NaHCO3, washed with water, dried over anhydrous sodium sulfate, and allowed to stand for more than 8h.The crude product is purified by column chromatography, and the product is recrystallized from dichloromethane or acetone to give a white powdery solid.Pure productN-(2-Trifluoromethyl-4-chlorophenyl)-2-[1-methyl-3-difluoromethyl-4-pyrazolecarboxamido]cyclohexanesulfonamide.
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 4h; 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (0.211 g, 1.2 mmol) was added to the reaction flask in that order.Dichloromethane (6 ml), N,N-dimethylformamide (2 drops),Add oxalyl chloride (1 g, 8 mmol),The reaction solution was stirred at room temperature for 4 hours. The solvent is then removed by rotary evaporation to give <strong>[176969-34-9]3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid</strong> chloride.This was dissolved in dichloromethane (2 mL) for use.Then 4-fluoro-2-(2-pentyloxy)aniline (0.197 g, 1 mmol) was added to the reaction flask and triethylamine (0.13 mL) was added.Further, a solution of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride was added dropwise to the reaction flask, and the mixture was stirred at room temperature for 16 hours.Then after monitoring the reaction by thin layer chromatography,Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with brine and dried over anhydrous sodium sulfate.Obtained 0.298 g of white solid.The yield was 83.94%.
With oxalyl dichloride; N,N-dimethyl-formamide; In toluene; <strong>[176969-34-9]3-(difluoromethyl)-1-methyl-1H-pyrazol-4-carboxylic acid</strong> obtained by example 2 is treated with oxalyl chloride (1.25 eq) in toluene, and a few drops of dimethylformamide are added. The mixture is concentrated under reduced pressure to yield the carboxyl chloride.
With thionyl chloride; for 4.5h;Reflux; 1-Methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid of formula (III) (7.76 g, 40 mmol) and reflux of thionyl chloride (47.6 g, 0.4 mol) After 4 hours, when the reaction system became a pale yellow transparent liquid, the reaction was continued for 30 min, the reaction was stopped, and after cooling to room temperature, distillation under reduced pressure gave 1-methyl-3-difluoromethyl-1H-pyrazole-4-yl chloride. 1-Methyl-3-difluoromethyl-1H-pyrazole-4-yl chloride (2 mmol) was added to 15 ml of dichloromethane, and phenylmethylamine (2·lmmol) was added, followed by slow dropwise addition of triethylamine ( 0.3g, 3mmol) stirred at room temperature overnight; TLC (EpsilonAlpha: RhoEpsilon = 2:1 (7)), after completion of the reaction, extract three times with dichloromethane / water = 1:1 (V) system, concentrate the organic layer, toluene or 75% Ethanol extraction, column chromatography (EpsilonAlpha: PE = 2:1 (V)) gave N-benzyl-1-methyl-3-(difluoromethyl)-1H-pyrazole as shown in (K11) 4-carboxamide
With thionyl chloride; N,N-dimethyl-formamide; In toluene; at 20℃; for 5h;Reflux; Will be 18 grams (0.1 mole)<strong>[176969-34-9]3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid</strong>Add 30 ml of toluene10 drops of DMF, 30 g (0.25 mol) of thionyl chloride was added dropwise at room temperature.Then, the temperature was refluxed for 5 hours.Remove the solvent by rotary evaporator to get reddish brown3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride.
With sulfuryl dichloride; for 3h;Reflux; 3-(difluoromethyl)-1 -methyl-i H-pyrazole-4-car-boxylic acid (2 g, 11.36 mmol) was dissolved in 20 mL sulthryl dichloride, and then heated to reflux for 3 h, the excessive sulfuryl dichloride was evaporated under reduced pressure to get 3-(difluoromethyl)-i -methyl- iH-pyrazole-4- carbonyl chloride, and then the carbonyl chloride was dissolved in 30 mL dichloromethane for the following reaction. To a cooled solution of (3-aminophenyl)methanol (1.4 g, 11.36 mmol) dissolved in 20 mL dichloromethane and 5 mL triethylamine was added slowly the solution of the carbonyl chloride at 0-5 C. Afier the reaction was stirred for 6 h at room temperature, analysis by Thin-Layer Chromatography showed complete conversion to product, the excessive solvent was evaporated under reduced pressure. the residual was purified by column chromatography on silica gel (eluent: ethyl acetate:petroleum ether=i:3; silica gel: 100-140 mesh, Qingdao Marine Chemical Co., Ltd.) to obtain 3-(di- fluoromethyl)-N-(3-(hydroxymethyl)phenyl)- i-methyl-i Hpyrazole-4-carboxamide (2.32 g) as white solid with yield of 73%. ?H NMR (300 MHz, CDC13) oe (ppm): 4.11 (s, 3H),4.73 (s, 2H), 7.16-7.81 (m, 6H).
With thionyl chloride; for 4h;Reflux; A mixture of <strong>[176969-34-9]3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid</strong> 3 (1.45 g, 7.50 mmol) and thionyl chloride (3.57 g, 30 mmol) was refluxed for 4 h. After the reaction was completed, the excess thionyl chloride was removed. The yellow liquid acyl chloride 4 was given and used fornext step without further purification.
With oxalyl dichloride; N,N-dimethyl-formamide; In toluene; 3-(difluorochloromethyl)-1-methyl-1H-pyrazol-4-carboxylic acid obtained by example 7 or 4 is treated with oxalyl chloride (1,25 eq) in toluene, and a few drops of dimethylformamide are added. The mixture is concentrated under reduced pressure to yield the carboxyl chloride
With oxalyl dichloride; N,N-dimethyl-formamide; In toluene; Example 6 <strong>[176969-34-9]3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid</strong> chloride <strong>[176969-34-9]3-(difluoromethyl)-1-methyl-1H-pyrazol-4-carboxylic acid</strong> obtained by example 5 is treated with oxalyl chloride (1,25 eq) in toluene, and a few drops of dimethylformamide are added. The mixture is concentrated under reduced pressure to yield the carboxyl chloride.
With oxalyl dichloride; N,N-dimethyl-formamide; In toluene; 3 -(difluorochloromethyl)-l -methyl- lH-pyrazol-4-carboxylic acid obtained by example 5 is treated with oxalyl chloride (1,25 eq) in toluene, and a few drops of dimethylformamide are added. The mixture is concentrated under reduced pressure to yield the carboxyl chloride.
With thionyl chloride; for 0.5h;Reflux; Add a <strong>[176969-34-9]1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid</strong> (30.0 mmol) and 10 mL of sulfoxide to a 100 mL reaction flask, and heat to reflux. After waiting for the reaction solution to change from turbid to clear, continue to react for 30 minutes.Stop heating and concentrate to remove excess sulfoxide,1-methyl-3-difluoromethyl-1H-pyrazole-4-formyl chloride represented by the formula (V-1) was obtained, and it became a solid after cooling.
With thionyl chloride; for 0.5h;Reflux; <strong>[176969-34-9]1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid</strong> (30.0 mmol) represented by formula (III-1) is mixed with 10 mL of dichlorosulfoxide and heated to reflux to react. When it is a pale yellow transparent liquid, the reaction is continued for 30 minutes, the reaction is stopped, and the excess thionyl chloride is concentrated to remove 1-methyl-3-difluoromethyl-1H-pyrazole-4-formyl chloride. 10 ml of dichloromethane was added to the prepared 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxyl chloride, and they were mixed uniformly to obtain solution A for use.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h; In a 50 mL eggplant-shaped bottle, add <strong>[176969-34-9]3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid</strong> (0.707 g, 4.01 mmol), add dichloromethane (20 mL), and add oxalyl chloride (1.29 g , 9.96mmol), add 1 drop of N, N-dimethylformamide dropwise, stir at reflux at room temperature, you can clearly see that the reaction solution gradually changed from turbid to clear, TLC followed the reaction, and the reaction ended after 1 hour. The solvent was spin-dried to obtain Intermediate 1, which was dissolved again with dichloromethane (10 mL) and set aside.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 1.66667h; The above compound, acid chloride A, was prepared as follows: (0147) [0083] 3-(Difluoromethyl)-1 -methyl-1 H-pyrazole-4-carboxylic acid (106 mg, 0.60 mmol) was dissolved in 3.0 ml. dry CH2CI2, then cooled to 0 C. Oxalyl chloride (50 mI_, 0.60 mmol) was added dropwise, followed by the addition of 5 mI_ dry DMF. The reaction mixture was stirred 10 min at 0 C before removing the cold bath and stirring an additional 1.5 hrs at room temp; reaction vessel was vented periodically in first 30 min following DMF addition to account for gas evolution. This stock solution was suitable for use in any procedure that calls for acid chloride A. 1H NMR (CDCI3, 500 MHz): d = 8.07 (s, 1 H, pyr), 6.93 (t, 1 H, JCF = 54.3 Hz, -CHF2), 4.01 (s, 3H, -NMe) ppm.

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  • 3
  • [ 6168-72-5 ]
  • [ 141573-96-8 ]
  • [ 1105713-22-1 ]
YieldReaction ConditionsOperation in experiment
90% With triethylamine; In dichloromethane; at 0 - 20℃; for 4h; a) Preparation of S-difluoromethyl-i-methyl-I H-pyrazole^-carboxylic acid (2-hvdroxy-1- methyl-ethvD-amide:At 00C1 a solution of 38.9g 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carbonyl chloride (0.2mol) in 100ml dichloromethane is added dropwise to a stirred solution of 15g alaninol (0.2mol) and 25g triethylamine (0.25mol) in 400ml dichloromethane. The reaction mixture is stirred for 1h at ambient temperature and then allowed to stand for 3h at ambient <n="39"/>temperature. After removal of the solvent the residue is purified by flash chromatography over silica gel 40Og (eluent: ethyl acetate/methanol 19:1). 42g (90% of theory) of 3- difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide is obtained in form of a solid (mp. 81-87CC).1H NMR (400MHz, CDCI3): delta 1.23-1.26(d,3H), 2.97(s,1 H1OH), 3.57-3.73(ddd,2H),3.94(s,3H), 4.17-4.23(m,1H), 6.57(s,1 H), 6.75-7.02(t,1H), 7.90(s,1 H).MS [M+H]+ 234.
90% With triethylamine; In dichloromethane; at 20℃; Example P8: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazol-4-yl)-4-methyl-2,2-dioxo- 2-lambda-*6*-? ,2.31oxathiazolidin-3-yl)-methanone a) Preparation of S-difluoromethyl-i-methyl-I H-pyrazole^-carboxylic acid (2-hvdroxy-1- methyl-ethvD-amide: At 00C, a solution of 38.9g 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carbonyl chloride (0.2mol) in 100ml dichloromethane is added dropwise to a stirred solution of 15g alaninol (0.2mol) and 25g triethylamine (0.25mol) in 400ml dichloromethane. The reaction mixture is stirred for 1 h at ambient temperature and then allowed to stand for 3h at ambient temperature. After removal of the solvent the residue is purified by flash chromatography over silica gel 40Og (eluent: ethyl acetate/methanol 19:1 ). 42g (90% of theory) of 3- difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide is obtained in form of a solid (mp. 81-87C).1H NMR (400MHz, CDCI3): delta 1.23-1.26(d,3H), 2.97(s,1 H,OH), 3.57-3.73(ddd,2H), 3.94(s,3H), 4.17-4.23(m,1 H), 6.57(s,1 H), 6.75-7.02(t,1 H), 7.90(s,1 H). MS [M+H]+ 234
90% With triethylamine; In dichloromethane; at 0 - 20℃; for 4h; Example P4: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid (2- hvdroxy-1 -methyl-ethvD-amide: At a temperature of 00C, a solution of 38.9g 3-difluoromethyl-1-methyl-1 H-pyrazole-4- carbonyl chloride (0.2mol) in 100ml dichloromethane is added dropwise to a stirred solution of 15g alaninol (0.2mol) and 25g triethylamine (0.25mol) in 400ml dichloromethane. The reaction mixture is stirred for 1 h at ambient temperature and then allowed to stand for 3h at ambient temperature. After removal of the solvent the residue is purified by flash chromatography over silica gel 40Og (eluent: ethyl acetate/methanol 19:1 ). 42g (90% of theory) of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid (2-hydroxy-1-methyl- ethyl)-amide is obtained in form of a solid (mp. 81-87C).1H NMR (400MHz, CDCI3): delta 1.23-1.26(d,3H), 2.97(s,1 H,OH), 3.57-3.73(ddd,2H), 3.94(s,3H), 4.17-4.23(m,1 H), 6.57(s,1 H), 6.75-7.02(t,1 H), 7.90(s,1 H). MS [M+H]+ 234.
90% With triethylamine; In dichloromethane; at 20℃; a) Preparation of S-difluoromethyl-i-methyl-I H-pyrazole^-carboxylic acid (2-hydroxy-1- methyl-ethvD-amide: At 00C, a solution of 38.9g 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carbonyl chloride (0.2mol) in 100ml dichloromethane is added dropwise to a stirred solution of 15g alaninol (0.2mol) and 25g triethylamine (0.25mol) in 400ml dichloromethane. The reaction mixture is stirred for 1 h at ambient temperature and then allowed to stand for 3h at ambient temperature. After removal of the solvent the residue is purified by flash chromatography over silica gel 40Og (eluent: ethyl acetate/methanol 19:1 ). 42g (90% of theory) of 3- difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide is obtained in form of a solid (mp. 81-87C).1H NMR (400MHz, CDCI3): delta 1.23-1.26(d,3H), 2.97(s,1 H,OH), 3.57-3.73(ddd,2H), 3.94(s,3H), 4.17-4.23(m,1 H), 6.57(s,1 H), 6.75-7.02(t,1 H), 7.90(s,1 H). MS [M+H]+
With triethylamine; In dichloromethane; at 0 - 20℃; for 4h; General procedure: To a solution of substituted 2-aminoethan-1-ol (50 mmol) andEt3N (6.06 g, 60 mmol) in CH2Cl2 (100 mL), 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride 4 (4.73 g, 50 mmol) inCH2Cl2 (30 mL) was added dropwisely under 0e5 C for 1 h. Thenthe mixture was vigorously stirred at ambient temperature for 3 h,then evaporated under reduced pressure and residue was purifiedby chromatography using EtOAc to afford the title compounds. 3-(difluoromethyl)-N-(1-hydroxypropan-2-yl)-1-methyl-1H-pyrazole-4-carboxamide 5a White solid, yield 89.9%, 1H NMR(400 MHz, CDCl3), delta 1.25 (d, J 6.8 Hz, 3H, CH3), 3.60-3.71 (m, 2H,CH2), 3.90 (s, 3H, CH3), 4.20-4.31 (m, 1H, NCH), 6.52 (brs, 1H, NH),6.85 (t, J 54.2 Hz, 1H, CHF2), 7.90 (s, 1H, pyrazolyl-H); S-3-(difluoromethyl)-N-(1-hydroxypropan-2-yl)-1-methyl-1H-pyrazole-4-carboxamide 5b White solid, yield 92.3%, m.p. 81-82 C, 1HNMR (400 MHz, CDCl3), delta 1.24 (d, J 6.8 Hz, 3H, CH3), 3.60 (dd,J 6.2, 6.2 Hz, 1H, CH2), 3.74 (dd, J 6.2, 6.2 Hz, 1H, CH2), 3.93 (s,3H, CH3), 4.18e4.24 (m, 1H, NCH2), 6.52 (brs, 1H, NH), 6.85 (t,J 54.2 Hz, 1H, CHF2), 7.94 (s, 1H, pyrazolyl-H); 13C NMR (150 MHz,CDCl3), delta 16.88, 39.52, 48.25, 67.28, 111.74, 116.63, 135.18, 142.88,161.90; 3-(difluoromethyl)-N-(1-hydroxy-2-methylpropan-2-yl)-1-methyl-1H-pyrazole-4- carboxamide 5c White solid, yield 91.4%,1H NMR (400 MHz, CDCl3), delta 1.37 (s, 6H, 2CH3), 3.66 (s, 2H, CH2),3.92 (s, 3H, CH3), 6.48 (brs, 1H, NH), 6.79 (t, J 54.2 Hz, 1H, CHF2),7.90 (s, 1H, pyrazolyl-H); 3-(difluoromethyl)-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-4-carboxamide 5d White solid, yield 90.2%, 1HNMR (400 MHz, CDCl3), delta 3.56 (t, 2H, NCH2), 3.79 (t, 2H, CH2O), 3.92(s, 3H, CH3), 6.80 (brs, 1H, NH), 6.88 (t, J 52.0 Hz, 1H, CHF2), 7.91 (s,1H, pyrazolyl-H).

  • 4
  • [ 141573-96-8 ]
  • [ 89763-88-2 ]
  • [ 31828-71-4 ]
  • [ 1105713-18-5 ]
  • [ 1105713-19-6 ]
YieldReaction ConditionsOperation in experiment
1: 18% 2: 63% With triethylamine In dichloromethane at 0 - 20℃; for 3h; P2 Example P2: Preparation of 3-difluoromethyl-1 -methyl- 1 H-pyrazole-4-carboxylic acid f2-(2,6- dimethyl-phenoxy)-1-methyl-ethyl1-amide (compound 1.166) and 3-difluoromethyl-1-methyl- 1 H-pyrazole-4-carboxylic acid f2-(4-bromo-216-dimethyl-phenoxy)-1 -methyl-ethyli-amide (compound 1.168):compound 1.166 compound 1.168At 00C, a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.29g; 1.5 mmol) in dichloromethane (3ml) is added dropwise to a stirred solution of 0.35g (1.5 mmol) of a 4:1-mixutre of 2-(4-bromo-2,6-dimethyl-phenoxy)-1-methyl-ethylamine (compound Z1.168) and 2-(2,6-dimethyl-phenoxy)-1-methyl-ethylamine (compound Z1.166), which is prepared as described in example P6, and triethylamine (0.3g; 3mmol) in dichloromethane (20ml). The reaction mixture is stirred for 1 h at ambient temperature and then allowed to stand for 2h. The reaction mixture is washed with 1 M NaOH (10ml) and 1M HCI (10ml) and then dried over Na2SO4. After removal of the solvent, 0.65g of a residue remained. Both reaction products are isolated by column-chromatography (column from Waters, RP PrepC18, 10μm, 50mm x 250mm; solvents: A = acetonitrile, B = water; gradient: 50% to 0% B in 15 min; flow rate: 2.0 ml/min): a) 90mg (18% of theory) of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid [2-(2,6- dimethyl-phenoxy)-1-methyl-ethyl]-amide (compound 1.166) is obtained in the form of a solid (m.p.142-146°C). Retention time for this compound is 10.78min.1H NMR (400MHz, CDCI3): δ 1.46-1.48(d,3H), 2.21 (2s,6H), 3.77-3.87(ddd,2H), 3.94(s,3H), 4.47-4.53(m,1 H), 6.76-7.03(t,1 H), 6.79(s,1 H), 6.91 (d,1 H), 7.00(d,2H), 7.93(s,1 H). MS [M+H]+ 338. b) 390mg (63% of theory) of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid [2-(4- bromo-2,6-dimethyl-phenoxy)-1-methyl-ethyl]-amide (compound 1.168) is obtained in the form of a solid (m.p.119-121 °C). Retention time for this compound is 12.53min.1H NMR (400MHz, CDCI3): δ 1.44-1.46(d,3H), 2.21(2s,6H), 3.72-3.85(ddd,2H), 3.89(s,3H), 4.46-4.51 (m,1 H), 6.76(s,1 H), 6.77-7.03(t,1 H), 7.11 (s,1 H), 7.93(s,1 H). MS [M+H]+ 416/418.
  • 5
  • [ 141573-96-8 ]
  • [ 72784-42-0 ]
  • [ 1192017-84-7 ]
YieldReaction ConditionsOperation in experiment
22.0% With triethylamine; In dichloromethane; at 5 - 20℃; for 17h; b) Preparation of 5-(3-(difluoromethyl)-1-methyl-1 H-pyrazol-4-yl)-6-oxa-4-aza- spiro[2.41)hept-4-en-7-one: <n="31"/>A suspension of 1-amino-cyclopropane carboxylic acid methylester hydrochloride (1.Og; 6.59 mmol) in CH2CI2 (80 ml) is cooled to 5°C under argon atmosphere. 3-difluoromethyl-1- methyl-1 H-pyrazole-4-carbonyl chloride (2.56g; 13.19 mmol) in CH2CI2 (20 ml) and then triethylamine (2.75 ml; 19.79 mmol) is added. The reaction mixture is stirred at 5-100C during 2 hours and then the cooling bath is removed and stirred at ambient temperature for 15 hours. The reaction mixture is diluted with CH2CI2 (40 ml) and extracted with saturated solution of K2CO3 (1x120 ml), 10percent HCI (1x120 ml), water (1x150 ml) and dried with anhydrous Na2SO4. After concentration under reduced pressure the crude product is purified by column chromatography over silica gel (eluent: ethyl acetate). 0.36g (22.0percent of theory) of 5-(3-(difluoromethyl)-1-methyl-1 H-pyrazol-4-yl)-6-oxa-4-aza-spiro[2.4])hept-4-en- 7-one is obtained in form of a white solid (m.p. 125-127°C). 1H NMR: (CDCI3, 300MHz):1.73-1.79(m, 2H, CH2); 1.82-1.88(m, 2H, CH2); 4.01 (s, 3H, CH3-N-Har); 7.12(t, 1 H, J= 53.7Hz, CHF2); 7.88(s, 1 H, H-Har).
  • 6
  • [ 141573-96-8 ]
  • [ 915416-45-4 ]
  • [ 907204-31-3 ]
YieldReaction ConditionsOperation in experiment
92% In toluene; at 0 - 85℃; under 300.03 Torr;Product distribution / selectivity; Example 1 Synthesis of N-(3',4'5'-trifluorobiphenyl-2-yl)-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxamide 100.0 g (0.504 mol, 98% pure) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride were dissolved at 25 C. in 257.2 g of toluene. The solution was evacuated to 400 mbar and heated to 85 C. Subsequently, within 3 hours, 492.8 g (0.499 mol, 23% strength) of toluenic <strong>[915416-45-4]3',4',5'-trifluorobiphenyl-2-ylamine</strong> solution were metered in, after which stirring was continued for another 1 hour. After venting and cooling to 25 C. with a ramp of 10 C/h, the mixture was stirred overnight. Subsequently, the mixture was cooled to 0 C., and the solid constituents were filtered off, washed with cold toluene and dried at 80 C. under reduced pressure. The yield (without further processing of the mother liquor) was 177.7 g (92%).
92% With pyridine; In toluene; at 55℃; for 0.166667h; A solution of 3 ', 4', 5'-trifluorobiphenyl-2-amine (0.45 mmol, 100 mg) and pyridine (0.81 mmol, 65 muL) were dissolved in 1 mL of toluene and the solution was heated to 55 C. A solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid chloride (0.45 mmol, 87.9 mg) in 300 muL of toluene was added dropwise over 10minutes and the reaction mixture was further stirred at 55 C Stir. The solution was heated to 70 C after theend of the reaction and washed with 2N HCl, saturated sodium bicarbonate solution and water. After cooling thesolution, the solvent was removed under reduced pressure and the resulting crude product was purified bycolumn chromatography on silica gel (hexane / EtOAc = 2: 1) to give N- (3 ', 4' 5-yl) -3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxamide (0.41 mmol, 158 mg, 92%).
With pyridine; In toluene; at 45 - 55℃; for 2h;Product distribution / selectivity; 9,55 kg 3',4',5'-trifluoro[1 ,1'-biphenyl]-2-yl-amine (I) were dissolved in 51 ,4 kg toluene and 6 kg pyridine were added. The mixture was stirred at 45C and 8.3 kg 3-(difluoromethyl)-1-methyl-1 H-pyrazole-4-carbonyl chloride (II) were dosed during one hour. Due to the exothermic nature of the reaction, the temperature raised to 55C. Post-reaction by stirring for 1 hour at 55C followed. Three extractions at 85C with 16 liter hydrochloric acid (5%), 14 liter sodium hydrogen carbonate (8%), and 14 liter deionized water followed. The resulting clear solution in toluene was cooled from 85C with a rate of 100C per hour to 00C. Around 75C, the first turbidity was observed, and at 75C and 73C, respectively, the batch was seeded with 10 g 3-(difluoromethyl)-1- methyl-N -(3',4',5'-trifluoro[1 ,1'-biphenyl]-2-yl)-1 H-pyrazole-4-carboxamide (III) each (>98% form B). The resulting slurry was filtered at 00C over a process filter and the filter cake was washed with 10 kg toluene at 00C. After drying in the drying cabinet at 800C and 20 mbar for 12 hours, 13.5 kg 3-(difluoromethyl)-1-methyl-N -(3',4',5'- trifluoro[1 ,1 '-biphenyl]-2-yl)-1 H-pyrazole-4-carboxamide (III) of >99.5% purity (GC, HPLC, NMR) was isolated. Using powder diffractometry (PXRD) and Fourier-Transform solid state infrared spectrometry (FT-IR) it was proven that the material consists to >98% of form B.
With triethylamine; In tetrahydrofuran; at 60℃; for 16h; General procedure: (1,3 mmol) 3',4?-dichloro-5-fluoro-l,r-biphenyl-2-amine and (1,56 mmol) 3- (difluorochloromethyl)-l -methyl- 1 H-pyrazo l-4-carboxylic acid chloride obtained by Example 9 are solved in 6 ml tetrahydrofuran and mixed with 2,6 mmol triethylamine. The mixture is stirred for l6h at 60C. The mixture is concentrated and chromatographed on silica using cyclohexane / acetic acid ethyl ester to yield Bixafen. Fluxapyroxad is obtained using the procedure of example 10, wherein 3',4',5'-trifluorobiphenyl-2-amine is used instead of 3',4'-dichloro-5- fluorobiphenyl-2-amine.

  • 7
  • [ 141573-96-8 ]
  • [ 1204-44-0 ]
  • [ 188425-85-6 ]
YieldReaction ConditionsOperation in experiment
73% In toluene; xylene; at 10 - 95℃; under 150.015 Torr; Example 8 Synthesis of 2-chloro-N-(4'-chlorobiphenyl-2-yl)nicotinamide 100.0 g (0.557 mol, 98% pure) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride were dissolved at 25 C. in 80.0 g of toluene. The solution was evacuated to 200 mbar and heated to 95 C. Subsequently, within 2.5 hours, 396.8 g (0.541 mol, 28% strength) of xylenic 4'-chlorobiphenyl-2-ylamine solution were metered in and the reaction mixture was stirred for a further 1 hour. After venting and cooling to 87 C., the mixture was seeded with 1 g of 2-chloro-N-(4'-chlorobiphenyl-2-yl)nicotinamide and the temperature was maintained for 1 hour. Subsequently, the mixture was cooled to 25 C. with a ramp of 5 C/h. After further cooling to 10-15 C., the solids were filtered off, washed with cold xylene and dried at 80 C. under reduced pressure. The yield (without further processing of the mother liquor) was 166.4 g (73%). HPLC shows the desired product and the diacylated product in a ratio of 85:15 area %.
  • 8
  • [ 141573-96-8 ]
  • [ 61855-43-4 ]
  • [ 1383809-87-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine / 1,2-dichloro-ethane / 3 h / Reflux 2: sulfuric acid; water / 0.5 h / 60 °C
Multi-step reaction with 2 steps 1: triethylamine / 1,2-dichloro-ethane / 3 h / Reflux 2: sulfuric acid / water / 0.5 h / 60 °C
  • 9
  • [ 141573-96-8 ]
  • [ 61855-43-4 ]
  • N-(3-difluoromethyl-1-methyl-1H-4-pyrazolecarbonyl)-6-fluoro-2,2,4-trimethyl-1,2,3,4-tetrahydro-quinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In 1,2-dichloro-ethane for 3h; Reflux; 1 A solution of 40 g of 3- (difluoromethyl) -1-methyl- lH-pyrazole-4-carbonyl chloride [compound of formula (III); MW 194,5] in 40 ml of dichloroethane , is dropped at room temperature in a solution of 34 g of 6-fluoro- 2,2, 4-trimethyl-l , 2, 3, 4-tetrahydroquinoline [compound of formula (V); MW 193] and 30 ml of triethylamine in 200 ml of dichloroethane. After stirring for 3 hours at reflux, the reaction mixture is poured in water (1,2 1) and extracted with dichloroethane . The organic layer is washed with 10% aqueous hydrochloric acid, anhydrified with sodium sulfate, concentrated under vacuum to afford 58 g of a crude solid product corresponding to N- (3- difluoromethyl-1 -methyl-1H-4 -pyrazolecarbonyl ) - 6- fluoro-2, 2, 4-trimethyl-l , 2, 3, 4-tetrahydroquinoline [compound of formula (II); GC-mass: M+ = 351] .
With triethylamine In 1,2-dichloro-ethane for 3h; Reflux; 1 EXAMPLE 1 Preparation of the 3-difluoromethyl-N-(7-fluoro-1,1,3-trimethyl-4-indanyl)-1-methyl-4-pyrazolecarboxamide (I) A solution of 40 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride [compound of formula (III); MW 194.5] in 40 ml of dichloroethane, is dropped at room temperature in a solution of 34 g of 6-fluoro-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline [compound of formula (V); MW 193] and 30 ml of triethylamine in 200 ml of dichloroethane. After stirring for 3 hours at reflux, the reaction mixture is poured in water (1.2 l) and extracted with dichloroethane. The organic layer is washed with 10% aqueous hydrochloric acid, anhydrified with sodium sulfate, concentrated under vacuum to afford 58 g of a crude solid product corresponding to N-(3-difluoromethyl-1-methyl-1H-4-pyrazolecarbonyl)-6-fluoro-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline [compound of formula (II); GC-mass: M+=351].
  • 10
  • [ 141573-96-8 ]
  • [ 54705-91-8 ]
  • N-(2-(1H-pyrazol-1-yl)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 0℃; for 0.5h;
  • 11
  • [ 252758-94-4 ]
  • [ 141573-96-8 ]
  • 3-(difluoromethyl)-1-methyl-N-(2-(4-methylpiperidin-1-yl)phenyl)-1H-pyrazole-4-carboxamide [ No CAS ]
  • 12
  • [ 141573-96-8 ]
  • [ 5192-04-1 ]
  • C14H12F2N4O [ No CAS ]
  • 13
  • [ 141573-96-8 ]
  • [ 102308-54-3 ]
  • C15H14F2N4O [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 0℃;
  • 15
  • [ 141573-96-8 ]
  • [ 28898-03-5 ]
  • C18H15F3N4O [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 0 - 20℃; for 10h; 4.2.2. General procedure for the synthesis of target compounds 9a, 9b and 9c General procedure: The main procedure is shown in Scheme 2. The raw products of compound 7 were synthesized via one-pot method in a flask containing compounds 5 (30 mmol), 6 (30 mmol), K2CO3 (15 mmol) and PEG1000 (0.45 mmol). The reactions were carried out under stirring at 185 °C and were monitored by TLC. After reactions completion, the desired diphenylamine derivatives 7 were obtained via column chromatographic purification. Next, compounds 7 (20 mmol), reductive iron powder (60 mmol), solid NH4Cl (60 mmol) and ethanol aqueous solution (75%, 50 mL) were added. The reactions proceeded with refluxing for 3 h at 90 °C and compounds 8 were obtained. Then, compound 3 (30 mmol) and SOCl2 (thionylchloride, 30 mL) were added. The mixture was heated to reflux at 90 °C for 3 h. Residual SOCl2 was removed by vacuum distillation in order to obtain compound 4. Finally, the primary amines 8 (10 mmol) dissolved in dichloromethane (CH2Cl2, 5 mL) and triethylamine(Et3N, 10 mL) were added. The mixture was cooled to 0 °C and compound 4 (20 mmol) dissolved in dichloromethane (CH2Cl2, 10 mL) was added dropwise under stirring at a temperature not exceeding 5 °C. The final mixture was stirred at room temperature for 10 h and the target compounds 9a, 9b and 9c were purified via column chromatography and recrystallization.
  • 16
  • [ 141573-96-8 ]
  • [ 68817-71-0 ]
  • C18H15ClF2N4O [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In dichloromethane; at 0 - 20℃; for 10.0h; General procedure: The main procedure is shown in Scheme 2. The raw products of compound 7 were synthesized via one-pot method in a flask containing compounds 5 (30 mmol), 6 (30 mmol), K2CO3 (15 mmol) and PEG1000 (0.45 mmol). The reactions were carried out under stirring at 185 C and were monitored by TLC. After reactions completion, the desired diphenylamine derivatives 7 were obtained via column chromatographic purification. Next, compounds 7 (20 mmol), reductive iron powder (60 mmol), solid NH4Cl (60 mmol) and ethanol aqueous solution (75%, 50 mL) were added. The reactions proceeded with refluxing for 3 h at 90 C and compounds 8 were obtained. Then, compound 3 (30 mmol) and SOCl2 (thionylchloride, 30 mL) were added. The mixture was heated to reflux at 90 C for 3 h. Residual SOCl2 was removed by vacuum distillation in order to obtain compound 4. Finally, the primary amines 8 (10 mmol) dissolved in dichloromethane (CH2Cl2, 5 mL) and triethylamine(Et3N, 10 mL) were added. The mixture was cooled to 0 C and compound 4 (20 mmol) dissolved in dichloromethane (CH2Cl2, 10 mL) was added dropwise under stirring at a temperature not exceeding 5 C. The final mixture was stirred at room temperature for 10 h and the target compounds 9a, 9b and 9c were purified via column chromatography and recrystallization.
  • 17
  • [ 141573-96-8 ]
  • [ 100953-52-4 ]
  • C18H15BrF2N4O [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 0 - 20℃; for 10h; 4.2.2. General procedure for the synthesis of target compounds 9a, 9b and 9c General procedure: The main procedure is shown in Scheme 2. The raw products of compound 7 were synthesized via one-pot method in a flask containing compounds 5 (30 mmol), 6 (30 mmol), K2CO3 (15 mmol) and PEG1000 (0.45 mmol). The reactions were carried out under stirring at 185 °C and were monitored by TLC. After reactions completion, the desired diphenylamine derivatives 7 were obtained via column chromatographic purification. Next, compounds 7 (20 mmol), reductive iron powder (60 mmol), solid NH4Cl (60 mmol) and ethanol aqueous solution (75%, 50 mL) were added. The reactions proceeded with refluxing for 3 h at 90 °C and compounds 8 were obtained. Then, compound 3 (30 mmol) and SOCl2 (thionylchloride, 30 mL) were added. The mixture was heated to reflux at 90 °C for 3 h. Residual SOCl2 was removed by vacuum distillation in order to obtain compound 4. Finally, the primary amines 8 (10 mmol) dissolved in dichloromethane (CH2Cl2, 5 mL) and triethylamine(Et3N, 10 mL) were added. The mixture was cooled to 0 °C and compound 4 (20 mmol) dissolved in dichloromethane (CH2Cl2, 10 mL) was added dropwise under stirring at a temperature not exceeding 5 °C. The final mixture was stirred at room temperature for 10 h and the target compounds 9a, 9b and 9c were purified via column chromatography and recrystallization.
  • 18
  • [ 141573-96-8 ]
  • [ 30273-11-1 ]
  • C16H19F2N3O [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In 1,4-dioxane; at 20℃; General procedure: 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid (7.76 g, 40 mmol) represented by formula (III) was refluxed with thionyl chloride (47.6 g, 0.4 mol) for 4 hours. When the reaction system turns to a pale yellow transparent liquid, the reaction is continued for 30 min. The reaction is stopped, and after cooling down to room temperature, 1-methyl-3-difluoromethyl-1H-pyrazole-4-acyl chloride is obtained by distillation under reduced pressure. 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride (2 mmol) was added to 15 ml of dichloromethane, Phenylmethanamine (2.1 mmol) was added followed by slow triethylamine (0.3 g, 3 mmol) stirring overnight at room temperature; followed by TLC (EA:PE=2:1 (V)) until the reaction was complete with dichloromethane. Three times extraction with water=1:1 (V) system, concentration of organic layer, extraction with toluene or 75% ethanol, and column chromatography (EA:PE=2:1(V)) to obtain N-benzyl as shown in (K11). 1-Methyl-3-(difluoromethyl)-1H-pyrazole-4-carboxamide
With triethylamine; In 1,4-dioxane; at 20℃; General procedure: 1-Methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid of formula (III) (7.76 g, 40 mmol) and reflux of thionyl chloride (47.6 g, 0.4 mol) After 4 hours, when the reaction system became a pale yellow transparent liquid, the reaction was continued for 30 min, the reaction was stopped, and after cooling to room temperature, distillation under reduced pressure gave 1-methyl-3-difluoromethyl-1H-pyrazole-4-yl chloride. 1-Methyl-3-difluoromethyl-1H-pyrazole-4-yl chloride (2 mmol) was added to 15 ml of dichloromethane, and phenylmethylamine (2·lmmol) was added, followed by slow dropwise addition of triethylamine ( 0.3g, 3mmol) stirred at room temperature overnight; TLC (EpsilonAlpha: RhoEpsilon = 2:1 (7)), after completion of the reaction, extract three times with dichloromethane / water = 1:1 (V) system, concentrate the organic layer, toluene or 75% Ethanol extraction, column chromatography (EpsilonAlpha: PE = 2:1 (V)) gave N-benzyl-1-methyl-3-(difluoromethyl)-1H-pyrazole as shown in (K11) 4-carboxamide
  • 19
  • [ 141573-96-8 ]
  • [ 43034-86-2 ]
  • N-(2-(3-(trifluoromethyl)phenylamino)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamid [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 0 - 20℃; for 3h;
  • 20
  • [ 141573-96-8 ]
  • [ 611-05-2 ]
  • 3-(difluoromethyl)-1-methyl-N-(3-methyl-4-nitrophenyl)-1H-pyrazole-4-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% With triethylamine; In dichloromethane; at 0 - 20℃; for 12h; <strong>[611-05-2]3-Methyl-4-nitroanilin</strong>e (2.28 g, 15.00 mmol) and triethylamine (3.03 g, 30.00 mmol) at 0 CAdd to 250 mL reaction flask containing dichloromethane (50 mL), then 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-methylThe acid chloride (3.49 g, 18.00 mmol) was slowly added dropwise to the system and stirred at room temperature for 12 hours. Quenched with water (50 mL), aqueous phaseThe organic layer was combined with EtOAc (EtOAc m.The residue was purified by silica gel column chromatography [petroleum ether / ethyl acetate (v / v) = 3/1], to give the title compound (yellow solid,3.39 g, yield: 73%).
  • 21
  • [ 141573-96-8 ]
  • [ 34231-22-6 ]
  • 3-(difluoromethyl)-N-(3-(hydroxymethyl)benzyl)-1-methyl-1H-pyrazole-4-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% With triethylamine; In dichloromethane; at 0 - 20℃; for 6h; To 3-(difluoromethyl)-i -methyl- 1H-pyrazole-4- carboxylic acid (1.5 g, 8.52 mmol) was added dropwise 20 mE sulthryl dichloride, and then heated to reflux for 3 h, the excessive sulfuryl dichloride was evaporated under reduced pressure to get 3-(difluoromethyl)-i -methyl- 1H-pyrazole-4- carbonyl chloride, and then the carbonyl chloride was dissolved in 30 mE dichloromethane for the following reaction. To a cooled solution of <strong>[34231-22-6](3-(aminomethyl)phenyl)methanol</strong> (1.17 g, 8.52 mmol) dissolved in 20 mE dichloromethane and 5 mE triethylamine was added dropwise the solution of the carbonyl chloride at 0-5 C. After the reaction was stirred for 6 h at room temperature, analysis by Thin-Layer Chromatography showed complete conversion to product, the excessive solvent was evaporated under reduced pressure. the residual was purified by column chromatography on silica gel (eluent: ethyl acetate:petroleum ether=i :3; silica gel: 100-140 mesh, Qingdao Marine Chemical Co., Ltd.) to obtain 3-(difluoromethyl)-N-(3-(hydroxymethyl)benzyl)-i - methyl-1H-pyrazole-4-carboxamide (1.8 g) as white solid with yield of 72%.
  • 22
  • [ 141573-96-8 ]
  • [ 203448-76-4 ]
  • 3-(difluoromethyl)-N-{2-(1,3-dimethylbutyl)phenyl}-1-methylpyrazole-4-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With triethylamine In chloroform at 0 - 25℃; for 1h; 1 2-(1,3-Dimethylbutyl)aniline (4.00 g, 22.7 mmol), triethylamine (2.50 g, 24.5 mmol), and chloroform (44 mL) were added to a separate vessel. Thereto, a chloroform solution (5 mL) of 3-(difluoromethyl)-1-methyl-pyrazole-4-carbonyl chloride prepared above was added at 0° C., and the resulting mixture was stirred at 25° C. for 1 hour. After confirming the completion of the reaction by TLC (thin layer chromatography), water was poured into the reaction mixture solution, and the solution was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent:ethyl acetate/n-hexane=1/1) to obtain the title compound (yielded: 6.50 g, yield: 85%) as a white solid.
  • 23
  • [ 141573-96-8 ]
  • [ 784-57-6 ]
  • C17H17F5N4O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
97% With triethylamine In dichloromethane at 0 - 20℃; for 0.5h; 6 Synthesis of Ib-1: General procedure: In a 100 mL single-neck flask, compound b-1 (0.43 g, 1.7 mmol) and triethylamine (0.42 mL, 2.1 mmol) were dissolved in 15 mL of DCM, and 3-(difluoromethyl)- was added dropwise under ice bath. 1-Methyl-1H-pyrazole-4-carbonyl chloride in DCM. After the addition is complete, move to room temperature to react. TLC monitoring, the reaction was completed in about 30 minutes. Silica gel column chromatography yielded 0.67 g of white solid with a yield of 97%.
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