Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 176969-34-9 | MDL No. : | MFCD11865267 |
Formula : | C6H6F2N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RLOHOBNEYHBZID-UHFFFAOYSA-N |
M.W : | 176.12 | Pubchem ID : | 18983008 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.33 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 35.52 |
TPSA : | 55.12 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.08 cm/s |
Log Po/w (iLOGP) : | 0.99 |
Log Po/w (XLOGP3) : | 0.41 |
Log Po/w (WLOGP) : | 1.57 |
Log Po/w (MLOGP) : | 0.6 |
Log Po/w (SILICOS-IT) : | 0.63 |
Consensus Log Po/w : | 0.84 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.37 |
Solubility : | 7.57 mg/ml ; 0.043 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.13 |
Solubility : | 12.9 mg/ml ; 0.0734 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.78 |
Solubility : | 29.6 mg/ml ; 0.168 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.63 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
117.6 g | at 130 - 155℃; | 200 g of ethyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate prepared according to Example 13 (GC purity: 92.8percent, 0.783 mol) and 69.50 gof1,3-dimethyl-2-imidazolidinone hexadecylHydrofluoric acid salts(0.160 mol) was put into a high-pressure reaction vessel, and the temperature was gradually raised to 130 ° C to 155 ° C.When the system temperature reaches 130 ~ 155 , to maintain the temperature,And kept at 130 ° C to 155 ° C for 7 to 12 hours.After the end of the reaction, the venting pressure, nitrogen purge, the exhaust gas is absorbed by the lye. Cooling to 60 ~ 80 , adding350 g of xylene and 60 g of water to dilute the reaction solution, slowly dropping 125.00 g of sodium hydroxide at a mass concentration of 30percentAqueous solution (the mass concentration refers to the mass of sodium hydroxide as a percentage of the total mass of the aqueous sodium hydroxide solution)After stirring at 70 ° C for 1 hour, the mixture was separated and the aqueous phase was acidified with a mass concentration of 36percent concentrated hydrochloric acid (said mass concentrationRefers to the mass of hydrogen chloride as a percentage of the total mass of concentrated hydrochloric acid) to pH = 1.0. Cooling to 10 ~ 25 , filtration, reallyDried to give 117.60 g of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (yield: 84.5percent, HPLC purity: 99.1percent;Isomer 5-difluoromethyl-1H-methylpyrazole-4-carboxylic acid HPLC purity: 0.05percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydroxide; In toluene; at 65℃; for 0.75h; | To the toluene layer was added 25% caustic soda solution159 g (0.994 mole) of the compound were added thereto, and the mixture was heated to 65 DEG C and stirred for 45 minutes. The aqueous layer was separated, and 54 g of water and 160.2 g (1.54 mole) of 35% hydrochloric acid were added to the toluene layer, followed by stirring at 85 for 15 minutes. After cooling to room temperature the resulting crystals were filtered, washed with 180 g of water and dried in vacuo at 60 & lt; RTI ID = 0.0 & gt;To obtain 155.8 g (yield 98%) of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid. |
95% | With sodium hydroxide; In ethanol; water; at 50 - 80℃; for 3h; | In a three-necked round bottom flask, 186 g of <strong>[141573-95-7]3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester</strong> (VII) was added.(0.91 mol), 900 ml of ethanol, and a solution of sodium hydroxide 44 g, (1.1 mol) dissolved in 900 ml of water, heated to 50C to 80C, and incubated for 3 hours, the reaction of the starting material was complete by TLC, and the ethanol was concentrated under reduced pressure to remove ethanol Add 100ml of toluene to extract, recover toluene in organic phase, cool the water phase to room temperature, adjust the PH value to 1-2 with 31% hydrochloric acid, cool to about 10C for 0.5 hours, filter and dry to obtain product 3- (Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid 6 (DFPA) 152 g, yield 95%. |
95% | With water; sodium hydroxide; | A solution of NaOH (1.2 g, 30 mmol) in water (50 mL) was added to <strong>[141573-95-7]ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate</strong> (5.1 g, 25 mmol). The mixture was stirred for overnight, then the mixture was acidified by using HCl, to afford the white solid 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid after filtration and drying with a yield of 95%, m. p. 204 C - 205 C, 1H NMR (400 MHz, CDCl3), delta 3.91 (s, 3H, N-CH3), 7.19 (t, JH-F 54.20 Hz, 1 H, -CHF2),8.31 (s, 1H, pyrazolyl-H), 12.73 (s, 1H, -COOH). |
95% | With water; sodium hydroxide; at 80℃; for 20h; | 30.8g (0.151mol)3-Fluoroalkyl-1-methylpyrazole-4-carboxylic acid ethyl ester (DFMPA) was put into the reaction flask, 100 g of water, 6.7 g of sodium hydroxide were added, and the reaction was stirred at 70 C for 2 hours. After the reaction was completed, Add hydrochloric acid dropwise to neutralize to pH 2, cool to 10 C, filter, wash with a little cold water, and dry to obtain 3-fluoroalkyl-1-methyl-1H-pyrazole-4-carboxylic acid (DFMPA) (such as (Expression V) 25.2 g, 95% yield, 99% purity by HPLC. |
87% | Preparation Example V.13-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylic acidA mixture of ethyl 3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylate (1.4 g, 52 mmol) and aqueous sodium hydroxide solution (10% strength, 3.1 g, 8 mmol) was stirred at 60 C. for 2 h. The reaction mixture was cooled to room temperature, and the pH was then adjusted to 1 using concentrated hydrochloric acid. The reaction mixture was cooled further to 0 C., resulting in the precipitation of a solid. The precipitated solid was filtered off, washed with cyclohexane and dried under reduced pressure. This gave 3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylic acid as a solid (amount: 0.8 g; yield: 87%). 1H-NMR (DMSO-d6): delta=3.9 (s, 2H), 7.2 (t, 1H), 8.35 ppm (s, 1H). | |
87% | Preparation Example V.13-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylic acidA mixture of ethyl 3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylate (1.4 g, 52 mmol) and aqueous sodium hydroxide solution (10% strength, 3.1 g, 8 mmol) was stirred at 60 C. for 2 h. The reaction mixture was cooled to room temperature, and the pH was then adjusted to 1 using concentrated hydrochloric acid. The reaction mixture was cooled further to 0 C., resulting in the precipitation of a solid. The precipitated solid was filtered off, washed with cyclohexane and dried under reduced pressure. This gave 3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylic acid as a solid (amount: 0.8 g; yield: 87%). 1H-NMR (DMSO-d6): delta=3.9 (s, 2H), 7.2 (t, 1H), 8.35 ppm (s, 1H). | |
83% | With potassium hydroxide; In water; | Ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate 2 (5.1 g, 25 mmol) and KOH (1.68 g, 30 mmol) were added to water (50 mL). The mixture was stirred for overnight, then acidified to pH = 1 using HCl, to give 3 as a white solid that was filtered off and dried with yield 83%, m.p. 200-201 C (Ref. m.p. 204-205 C) [38] , 1H NMR (400 MHz, CDCl3), delta 3.91 (s, 3H, N-CH3), 7.19 (t, J = 54.2 Hz, 1H, -CHF2), 8.31 (s, 1H, pyrazolyl-H), 12.73 (s, 1H, -COOH). |
Process step b1): 450mmol NaOH (in the form of a 30%(w/w) aqueous solution) is added and the reaction mixture is stirred for 45 minutes at 65C. The aqueous phase is isolated from the organic phase at 65C and added to a solution of 50 g water and 570mmol HCl (in the form of a 32%(w/w) solution), which is pre-heated to 95C. The reaction mixture is stirred for 10 minutes at 95C and a precipitate is formed. | ||
The preparation was carried out analogously to example 1, but in contrast to example 1, instead of recrystallization from hexane, the solid residue obtained after aqueous extractive work-up and removal of the ethyl acetate was processed further as follows:16 g of a 50% by weight strength aqueous sodium hydroxide solution and 100 ml of ethanol were added to the solid residue, and with stirring, the mixture was heated at reflux for 4 h. The solvent was then removed under reduced pressure and the aqueous residue obtained was adjusted to pH 1 using 10% hydrochloric acid. This caused the dicarboxylic acid to precipitate as a solid which was isolated by filtration. This gave 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid as a light-brown powder.1H-NMR (d6-DMSO, 400 MHz): delta=3.92 (s, 3H), 7.21 (t, 1H, J=53 Hz), 8.34 ppm (s, 1H). | ||
Example 1 (inventive)Preparation of ethyl 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylate at (-6O)0C and subsequent hydrolysis to 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid.43.8 g (0.33 mol) of methylhydrazine solution (34.7% by weight of methylhydrazine in water) and 270 g of ethanol (anhydrous, undenatured) were initially charged and cooled to (-6O)0C. Within 2 hours, at (-60)C, a freshly prepared solution of 71.1 g (0.3 mol) of ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate (93.7%) in 71 g of ethanol was added dropwise. This formed a suspension which was stirred at (-60)C for another hour and then warmed to 25-30C within 3 hours. The solution comprised 1 1.18% by weight of the desired ethyl 3-difluoromethyl 1-methyl-1 H-pyrazole-4- carboxylate and only 1.14% by weight of the undesired isomeric ethyl 5-difluoromethyl- 1-methyl-1 H-pyrazole-4-carboxylate (HPLC analysis, quantification with external Standard). The isomer ratio was 9.8 : 1. 252.5 g (0.45 mol) of 10% aqueous potassium hydroxide solution were metered and the reaction mixture was stirred at 600C for 3 hours. The solvent was then distilled off completely under reduced pressure and the remaining residue dissolved in 480 g of demineralized water. 100 g (0.877 mol) of cone, hydrochloric acid (32%) were added dropwise to the salt solution at 55C within 20 minutes, in the course of which the desired carboxylic acid crystallized out. The suspension was cooled to 3C and stirred at this temperature for a further 1 hour. The solid was filtered off and washed twice with 100 g of cold demineralized water (3C). After the drying (600C, 20 mbar), 45.1 g of 3- difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid were obtained in a purity of 98.6% by weight. The yield, based on the molar amount of ethyl 2-ethoxymethylene- 4,4-difluoro-3-oxobutyrate used, was 84.2%. | ||
Example P2: Preparation of 3 -difluoromethyl-1 -methyl- lH-pyrazole-4-carboxylic acid To the organic phase obtained in Pl 19 g water and 0.51 mol NaOH 30% were added and heated to 60-65 0C. The reaction mass was stirred during 45 minutes at 60-65 0C. The phases of the reaction mixture were separated at 60-65 0C. The alkaline water phase (product phase) was added to a solution of 20.0 g water and 0.54 mol of HCl 32% at 80- 85 0C. The reaction mass was stirred over 5-10 minutes at 80-850C. The suspension was cooled down from 80-85 0C to 0-5 0C. The suspension was filtered off and crystals washed 2 x with 42.5 g of water (0 0C, displacement-washing). The product was dried at 600C under reduced pressure. | ||
Example 2; Preparation of ethyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate with a Catalytic Amount of P-Toluenesulfonic Acid and Subsequent Hydrolysis to Give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid62 g (0.2 mol) of ethyl 4,4-difluoro-2-[1-{N-methyl-N'-[1-phenylmethylidene]hydrazino}methylidene]-3-oxobutyrate (prepared analogously to example 1, step 1.1., purity 99.1 area %) were initially charged together with 150 g of ethanol at 15 C. under a nitrogen atmosphere. 1.6 g (0.0083 mol) of p-toluenesulfonic acid monohydrate were added and the mixture was stirred at 25 C. for 15 hours and at 50 C. for 1 hour. The solution comprised 14.9% by weight of the desired ethyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate (HPLC analysis, quantification with external standard). The proportion of the isomeric ethyl 5-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate is only 0.069% by weight (corresponding to an isomer ratio of >200:1).168.3 g (0.3 mol) of 10% potassium hydroxide solution were then metered in and the reaction mixture was stirred at 60 C. for 3 hours. After cooling to 25 C., the phases were separated. The toluenic upper phase comprised mainly the benzaldehyde released. The lower aqueous phase comprised, as the main component, the potassium salt of the desired 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid. The toluene phase was washed twice more with 50 g each time of water. The combined water phases were acidified at 55 C. with 66 g (0.579 mol) of concentrated hydrochloric acid (32%) (pH<2), which precipitated the desired title compound. The solids were filtered off at 3 C. and washed with 132 g of cold water. After drying (60 C., 20 mbar), 32.1 g of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid were obtained in a purity of 99% by weight. The yield based on the molar amount of methylhydrazine or ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate used was 90.3%. The undesired 1,5-isomer is no longer detectable. | ||
The azinium salt (10.0 g, 29.9 mmol) was suspended in 50 mL of toluene. A solution of NaOH (1.44 g, 36.0 mmol) in 50 mL of water was added and the biphasic mixture was heated to 60 C. for 3 h. The mixture was then cooled to rt, the phases split and the aqueous phase extracted with 20 mL of toluene. The combined org. phases were used in the next step without further purification. To the solution of the aminal in toluene were added ethyl alpha-ethoxymethylene-4,4-difluoro-3-oxobutyrate (6.64 g, 29.9 mmol) and p-TsOH monohydrate (0.57 g, 3.0 mmol). The solution was stirred overnight at rt, then heated to 60 C. for one hour. The solution was then cooled to it and extracted with 30 mL sat. NaHCO3 solution. The org. phase was used in the next step without further purification. To the org. phase was added 10% KOH solution (24.1 g). The biphasic mixture was heated to 60 C. and the disappearance of the ester monitored by GC. When the ester had completely vanished, the solution was cooled to rt. The phases were then split and the aqueous phase was heated to 55 C. Then, 30% H2SO4 solution (16 g) were added and stirring continued for 60 min. The solution was then cooled to 5 C. and the precipitated product removed by filtration. The precipitate was washed with cold water and dried under reduced pressure overnight (p<20 mbar, 50 C.). The product was obtained as a yellow powder (2.87 g, 16.3 mmol, 55% yield based on the azinium salt). 1H NMR (500 MHz, DMSO-d6): delta (ppm)=8.33 (s, 1H); 7.22 (t, J=54 Hz, 1H); 3.93 (s, 3H). 13C NMR (125 MHz, DMSO-d6): delta (ppm)=163.0; 145.1 (t, J=24 Hz); 136.1; 113.0 (t, J=3 Hz); 109.6 (t, J=234 Hz); 39.2. 19F NMR (470 MHz, DMSO-d6): delta (ppm)=-126.0 (d, J=54 Hz). mp=205 C. Purity (cal. HPLC): 97.1% (0.4% iso-DFP acid) | ||
Benzaldehyde (24.0 g, 226 mmol) was dissolved in 240 mL of toluene. Hydrazine hydrate (5.0 g, 100 mmol) was added dropwise; the solution was heated to 90 C. and stirring was continued for 3 h. Then, a Dean-Stark apparatus was attached and water was removed by azeotropic distillation. The solution was then cooled to 70 C. and Me2SO4 (18.9 g, 150 mmol) was added. The solution was heated to 85 C. overnight. During that time a yellow precipitate formed. The mixture was cooled to 40 C. and 100 mL of toluene were added, followed by a solution of NaOH (8.0 g, 200 mmol) in 170 g of water. Die biphasic mixture was heated to 60 C. and stirred for further 3 h at that temperature. The solution was cooled to rt, the phases were separated and the aqueous phase was washed with toluene (50 mL). The organic phases were combined and used in the next step. To the afore prepared solution were added Ethyl alpha-ethoxymethylene-4,4-difluoro-3-oxobutyrate (20.0 g, 90.0 mmol), p-TsOH (0.9 g, 4.5 mmol) and water (1.62 g, 90.0 mmol). The mixture was heated to 60 C. for 3 h (at that time GC showed full conversion). After cooling to rt, the org. phase was extracted with sat. NaHCO3 solution (60 mL). To the organic phase was then added 10% KOH (101 g) and the biphasic mixture was heated to 60 C. for 3 h and stirred at rt overnight (on the next day GC showed complete saponification of the ester). The phases were split and the org. phase separated with 50 mL of water. The combined aqueous phases were warmed to 55 C. and 30% H2SO4 (59.0 g) was added. After stirring for 1 h at that temperature the solution was cooled to 5 C. and the precipitated acid was separated by filtration and washed with ice-cold water (2*25 mL). The product was dried under reduced pressure overnight (p<20 mbar, 50 C.). The product was obtained as a yellow powder (11.2 g, 63.5 mmol, 64% yield based on hydrazine). | ||
3.22 g | With sodium hydroxide; In water; toluene; at 65℃; for 0.75h; | Compound 3 was synthesized via two main steps. First, compound 1 (60 mmol) and triethyl orthoformate (120 mmol) were placed in a round-bottom flask containing acetic anhydride (180 mmol) as solvent. The mixture was refluxed at 110-130 C for 6 h and the reaction progress was monitored by TLC. A brown residue (i.e. compound 2) was obtained by vacuum distillation, used to remove impurities and solvents with low boiling points from the reaction mixture. Compound 2 was used as a reactant without further purification. Second, to a 50 mL round-bottom flask containing 30% methyl hydrazine hydrate (60 mmol) and a 30% NaOH (60 mmol) aqueous solution, a mixture of compound 2 (whole raw products of the first step) in 15-20 mL of toluene was added dropwise for 30 min at 15 C under stirring. The resulting mixture was stirred for another 10 min at 25 C. An aqueous solution consisting of 30% NaOH (80 mmol) was added and the resulting mixture was stirred at 65 C for 45 min. After reaction completion, the mixture was poured into a separatory funnel to separate the water layer. This aqueous phase was collected and added dropwise to an aqueous solution consisting of 30% HCl (90 mmol) at 95 C. After cooling to room temperature, the precipitate was filtered, washed with water, and was dried in vacuo to afford 3.22 g of compound 3 as a white powder. |
With water; sodium hydroxide; at 60℃; for 3h; | 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) 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid;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 water; sodium hydroxide; at 60℃; for 3h; | 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. | |
The alkali solution was warmed to 55 C, was added dropwise to the organic layer obtained in step c, the reaction 1h; then recovered the organic solvent, the aqueous layer was retained, the aqueous layer acidified at a temperature of 80 25min, natural cooling To 30 , then water-cooled to 15 , incubated for 30min, filtered and dried to obtain finished DFPA. | ||
With water; sodium hydroxide; at 60℃; for 3h; | Ethyl 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylate represented by the formula (II) (8.88 g, 40 mmol) was added to a 5% aqueous sodium hydroxide solution (100 ml). 60 C reaction for 3 hours, The reaction system is transparent, then neutralized with hydrochloric acid to adjust the pH to weakly acidic, solids are precipitated, and the reaction is stopped. The 1-methyl-3-difluoromethyl-1H-pyrazole represented by the formula (III) is obtained by suction filtration. 4-carboxylic acid. | |
With water; sodium hydroxide; at 60℃; for 3h; | Ethyl 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylate (8.88 g, 40 mmol) of the formula (II) was addedto a 5% aqueous sodium hydroxide solution (100 ml). The reaction was carried out at 60 C for 3 hours, until the reaction system was transparent, and then neutralized with hydrochloric acidto adjust the pH to weak acidity, and the solid was precipitated, the reaction was stopped, and the solution was filtered to obtain 1-methyl-3-difluoromethyl group represented by formula (III). -1H-pyrazole-4-carboxylic acid. | |
With water; sodium hydroxide; at 70℃; for 2h; | 27 g (0.132 mol) of 3-fluoroalkyl-1-methylpyrazole-4-carboxylic acid ethyl ester (EDFMPA) was put into a reaction flask, and 90 g of water was added,6g of sodium hydroxide,The reaction was stirred at 70 C for 2 hours, and the reaction was completed.Add hydrochloric acid dropwise to neutralize to pH 2,Cool to 10 C, filter,Wash with a small amount of cold water and dry to obtain 22 g of 3-fluoroalkyl-1-methyl-1H-pyrazole-4-carboxylic acid (DFMPA) (as shown in formula V).The yield was 95%, and the purity by HPLC was 99%. | |
With sodium hydroxide; In water; at 60℃; | Into a 100 mL reaction flask, add <strong>[141573-95-7]1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester</strong> (38.0 mmol) represented by formula (III-1) and 10% NaOH by mass. 30mL of aqueous solution,The temperature was raised to 60 C, and the reaction solution was transparent, and then naturally cooled to room temperature.Acid was added to the reaction solution to adjust the pH to about 2.0, and a large amount of solid was precipitated.After drying, 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid represented by the formula (IV-1) was obtained. | |
With water; sodium hydroxide; at 60℃; | In a 100 mL reaction flask, add <strong>[141573-95-7]1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester</strong> (38 mmol) represented by formula (II), and then add 10% by mass NaOH30mL of aqueous solution, heated to 60 C and stirred until the reaction solution was transparent, then naturally cooled to room temperature,Acid was added to the reaction solution to adjust the pH to about 2.0, and a solid was precipitated.After the filter residue is washed and dried,1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid represented by the formula (III) was obtained. | |
With water; sodium hydroxide; at 60℃; | In a 100 mL reaction flask, add <strong>[141573-95-7]ethyl 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylate</strong>(38 mmol) represented by formula (II), and then add 10% by mass 30mL NaOH aqueous solution, heated to 60 C and stirred until the reaction solution was transparent, and then naturally cooled to room temperature. The reaction solution was adjusted to pH about 2.0 by adding acid, a large amount of solid was precipitated, filtered by suction, and the filter residue was washed with water and dried to obtain the formula 1) -methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid. | |
With water; sodium hydroxide; at 60℃; | In a 100 mL reaction flask, add <strong>[141573-95-7]1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester</strong> (40 mmol) represented by formula (II-1), and then add a mass concentration of 10 30% NaOH aqueous solution, heated to 60 C and stirred until the reaction solution was transparent, then naturally cooled to room temperature, acid was added to the reaction solution to adjust the pH to about 2.0, a large amount of solid was precipitated, and filtered, and the filter residue was washed with water and dried to obtain the formula (III-1) 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid. |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used. | ||
Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used. | ||
Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used. |
Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used. | ||
Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used. | ||
Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used. | ||
Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used. | ||
Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used. | ||
Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; triethylamine; triphenylphosphine;tris(triphenylphosphonium)palladium(II)chloride; In 1-methyl-pyrrolidin-2-one; at 150℃; under 4500.45 - 5250.53 Torr;Product distribution / selectivity; | 0.31 g 4-Bromo-3-difluoromethyl-1-methyl-1 H-pyrazole, 0.82 g water, 9 g N-methylpyrrolidinone, 1 g triethylamine, 0.06 g tris(triphenylphosphonium)palladium(II)chloride and 0.12 g triphenyl phosphine were charged to a 50ml glass miniclave reactor fitted with a 10bar bursting disc, thermometer and gas feed. The system was pre-purged with carbon monoxide six times up to 7 bar - venting off slowly each time and agitating throughout. Finally the reactor was pressurised up to 6 bar. The system was agitated whilst heating up to 150C and the pressure maintained at 6-7 bar by venting as necessary. When the mixture had stabilised on temperature, and pressure, it was agitated overnight under these conditions. The following day the system was cooled, vented and the reactor contents evaporated as far as possible on a rotary evaporator. The resultant oil was quenched with an aqueous base and extracted with 3 x 25ml of ether. The combined ether extracts were washed with brine, dried over magnesium sulphate and concentrated under vacuo to yield a red/brown oil (0.5g). The aqueous base extracts were acidified and back extracted with 3 x 25ml of ether. The extracts were combined, dried over magnesium sulphate and concentrated under vacuo. Derivatised GC analysis showed that the desired 1, 3-pyrazole isomer (compound of formula I) was present in virtually all phases obtained from the work-up (HPLC analysis). Most of the product, and its isomer, were present in the ether extract from the initial base wash. The product was not isolated but compared to reference material by HPLC, derivatised GC and GCMS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Example P1 : Preparation of S-difluoromethyl-i-methyl-I H-pyrazole^-carboxylic acid [1- methyl-3-(2,4,6-trichloro-phenyl)-propyl1-amide (compound 1.004): To the suspension of S-difluoromethyl-i-methyl-I H-pyrazole^-carboxylic acid (190mg,1.08mmol) in 10ml dichloromethane under nitrogen environment few drops of DMF is added to make a clear solution. HOBT (248mg, 1.62mmol) is added at ambient temperature and after 20mins EDCI (310mg, 1.62mmol) is added to the above solution maintained at 0-50C. After 30 minutes 1-methyl-3-(2,4,6-trichloro-phenyl)-propylamine (300mg, 1.19mmol), which is prepared as described in example P5d, is added to the solution at ambient temperature followed by catalytic amount of DMAP. Reaction mixture is kept at ambient temperature for 3 hours for completion. Reaction mixture is diluted with water (15ml) and aq. layer is extracted with dichloromethane (3 x 30ml). Combined organic layer is washed with HCI (10ml, 1 N) followed by saturated NaHCO3 (10ml), water (20ml) and brine (15ml).Organic layer is dried over sodium sulfate and concentrated under vacuum to give brownish mass. Crude product is purified by silica-gel chromatography.0.14g (50% of theory) of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid [2-(4- acetyl-p-phenoxy)-1-methyl-ethyl]-amide (compound 1.004) is obtained in form of a white solid (m.p.100C).1H NMR: (CDCI3, 400MHz):7.93(s,1 H); 7.32(s,1 H); 6.94-6.67(t,J=54,1 H); 6.26(s,1 H); 4.31-4.24(m,1 H); 3.92(s,3H); 2.99-2.92(m, 2H);1.79-1.67(m,2H); 1.29-1.27(d, J=6.4,3H)MS [M+H]+ 410/412/414. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydroxide; In water; at 90 - 100℃; | A four-necked round bottom flask was charged with 31.4 gDifluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile, 80.0 g15% aqueous solution of sodium hydroxide, heated to 90-100 , to be detected after the reaction of raw materials,303 C was slowly added dropwise 233.6 g of 5% hydrochloric acid to a pH of less than 3,Slowly after the turbid liquid temperature dropped to room temperature, pumping filter washing,Dried to give 33.8 g of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, 99.0% purity and 95% yield. |
92% | [Example 21]; Hydrolysis: Conversion from Compound (XI) to Compound (XIII); To 40 ml of water containing 3.56 g of sodium hydroxide, 4.0 g of Compound (XI) was added, followed by allowing reacting at an external temperature of 95C for 4 hr. After the reaction came to completion, the reaction mixture was acidified by adding concentrated hydrochloric acid while cooling with ice. Then, the solution was stirred for 1 hour at room temperature and a precipitate was filtered. The resulted white solid was Compound (XIII) (4.11 g). The yield was 92%.Material data of compound (XIII) 1H NMR (DMSO-d6) delta3.91 (3H, s), 7.21 (1H, t, J = 53.7 Hz), 8.33 (1H, s) | |
92.1% | With water; sodium hydroxide; In methanol; for 2h;Reflux; | The reaction flask was charged with 95.3% of 1-methyl-3-difluoromethyl-4-pyrazolecarbonitrile (3.0 g, 8.7 mmol) represented by the formula (VI) and 30 mL of methanol in an amount of 95.3% Aqueous 20% sodium hydroxide solution (5.0 g, 25.0 mmol) was added dropwise, the reaction was continued for 2 h after the completion of the dropwise addition, TLC detection reaction was complete, the methanol was evaporated under reduced pressure, The aqueous phase is washed once with ethyl acetate, Concentrated hydrochloric acid pH to about 2 solid precipitation, ice water bath for 30 min, filtered, Take cake, ethanol and water recrystallization to give a white solid 1.4 g, HPLC content of 99.5% Yield 92.1%. |
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide; In water; toluene; at 70℃; for 8h; | In the preparation method of the pyrazole derivative of this embodiment, acetylmethylhydrazine is suspended in 200 g of toluene,Add 96.1g (1mol) of cyanide () and heat to reflux for 12 hours, The released dimethylamine is absorbed with hydrochloric acid, and toluene is distilled off. To the residue, add 200g of toluene, 100g of hexamethyldisilazane, 2g of trimethylchlorosilane, heat and reflux for 5 hours, and complete the reaction. Add 120g of triethylamine , Cool to 10C, pass difluoroacetyl fluoride (1.1mol), keep at 30C for 2 hours, Add 50g concentrated sulfuric acid, react at 20C for 10 hours, Add 200g of water, add 200g of water, stand still and separate. The organic layer is washed with 100g of water and concentrated to dryness.100g toluene and 120g water, 55g caustic soda,8g tetrabutylammonium bisulfate, react at 70C for 8 hours,Add hydrochloric acid dropwise to neutralize to pH about 1.5.Precipitate solid product, filter, wash, dry, product1-methyl-3-difluoromethyl-4-pyrazolecarboxylic acid120g. The reaction formula is as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 1,1,2,2-tetrafluoroethyldimethylamine (3.2 g, 22 mmol) in diethyl ether (10 ml) and dioxane (10 ml) was added dropwise, under a nitrogen atmosphere, at a temperature of from 0 to 5 C., a solution of BF3-etherate (49% BF3, 5.6 ml, 44 mmol). After the addition had ended, the reaction mixture was stirred for 5 min. Subsequently, pyridine (1.7 g, 22 mmol) and a solution of ethyl 3-(pyrrolidin-1-yl)acrylate (2.9 g, 20 mmol) in dioxane (2 ml) were successively added dropwise to the reaction mixture at a temperature of from 0 to 5 C. After stirring for 6 hours, the reaction mixture was added at a temperature of from 0 to 5 C. to a mixture of sodium hydroxide (4.4 g, 110 mmol) and methylhydrazine (1.4 g, 30 mmol) in water (75 ml), and then the mixture was stirred at room temperature for 3 h. The reaction mixture was freed of volatile constituents. The resulting residue was taken up in water (50 ml), washed with ethyl acetate and then brought to a pH of 2 with conc. hydrochloric acid. The aqueous phase was decanted off and discarded. The resulting slimy residue was taken up in a mixture of tetrahydrofuran and methyl tert-butyl ether, dried over sodium sulfate, filtered and freed from the solvent under reduced pressure. 3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid was obtained as a mixture with 5-difluoromethyl-1-methylpyrazole-4-carboxylic acid with a ratio of 2:1 in a yield of 60%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | To a solution of 1,1,2,2-tetrafluoroethyldimethylamine (3.2 g, 22 mmol) in diethyl ether (10 ml) and dioxane (10 ml) was added dropwise, under a nitrogen atmosphere, at a temperature of from 0 to 5° C., a solution of BF3-etherate (49percent BF3, 5.6 ml, 44 mmol). After the addition had ended, the reaction mixture was stirred for 5 min. Subsequently, pyridine (1.7 g, 22 mmol) and a solution of <strong>[1001-26-9]ethyl 3-ethoxyacrylate</strong> (2.9 g, 20 mmol) in dioxane (2 ml) were added dropwise successively to the reaction mixture at a temperature of from 0 to 5° C. After stirring at room temperature for 6 hours, the reaction mixture was added at a temperature of from 0 to 5° C. to a mixture of sodium hydroxide (4.4 g, 110 mmol) and methylhydrazine (1.4 g, 30 mmol) in water (75 ml) and then stirred at room temperature for 1 h. Subsequently, the reaction mixture was heated to 60° C. and stirred at this temperature for 0.5 h. The reaction mixture was freed of volatile constituents. The resulting residue was taken up in water (50 ml), washed with ethyl acetate and then brought to a pH of 2 with conc. hydrochloric acid. The precipitated solid was isolated by filtration, washed with water and dried under reduced pressure at a temperature of 50° C. Isomerically pure 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid was obtained in a yield of 50percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 1,1,2,2-tetrafluoroethyldimethylamine (30 g, 207 mmol) in diethyl ether (90 ml) and dioxane (90 ml) was added dropwise, under a nitrogen atmosphere, at a temperature of from 0 to 5° C., a solution of BF3-etherate (49percent BF3, 59.6 ml, 420 mmol). After the addition had ended, the reaction mixture was stirred for 5 min. Subsequently, pyridine (15.9 g, 201 mmol) and methyl 3-methoxyacrylate (22.3 g, 186 mmol) were successively added dropwise to the reaction mixture at a temperature of from 0 to 5° C. After stirring for 6 hours, a greasy solid formed, from which the supernatant solution was decanted off and discarded. The solid was then added at a temperature of from 0 to 5° C. to a mixture of sodium hydroxide (41.4 g, 1.035 mol) and methylhydrazine (38.6 g of a 35percent aqueous solution, 288 mmol) in water (665 ml) and then stirred at room temperature for 1 h. Subsequently, the reaction mixture was heated to 60° C. and stirred at this temperature for 0.5 h. The reaction mixture was freed of volatile constituents. The resulting residue was taken up in water (50 ml), washed with ethyl acetate and then brought to a pH of 2 with conc. hydrochloric acid. The solid precipitated at a temperature of 0° C. was isolated by filtration, washed with a little ice-cold water and dried under reduced pressure at a temperature of 40° C. 3-Difluoro-methyl-1-methylpyrazole-4-carboxylic acid was obtained as a mixture with 5-difluoro-methyl-1-methylpyrazole-4-carboxylic acid with a ratio of 85:15 in an amount of 10.1 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With manganese(II) acetate dihydrate; acetic acid; at 100℃; for 18h; | 0.1 mol (17.4 g) of 1- (3- (difluoromethyl) -1-methyl-i H-pyrazol-4-yl)ethanone was dissolved in 50 mL acetic acid, and the respective catalyticsystem was added. Air was bubbled into the solution and the solution was heated to 100C. The reaction was performed during 18 hours; the content of product 3- (difluoromethyl)- i-methyl-i H-pyrazole-4-carboxylic acid (DFMPA) was measured in the reaction mixture by HPLC. Amounts of catalysts are given in eq. in relation to the molar eq. i-(3-(difluoromethyl)-i-methyl-iH-pyrazol-4-yl)ethanone. Results are given in Table 1. |
98% | With sodium hypochlorite; sodium hydroxide; In water; at 70℃; for 2h; | In an air atmosphere, at room temperature (25 ), the sodium hydroxide 0.72g (18.0mmol), 8% aqueous sodium hypochlorite solution 16.2g (17.5mmol) was added the compound by the method of the aforementioned [Example 2] obtained ( 5-1) 1.01g (5.7mmol), stirred at 70 2 hours.The reaction solution was ice-cooling, followed by addition of a saturated aqueous solution of sodium sulfite and 5ml quenched, the aqueous phase was added 33g of concentrated hydrochloric acid, extracted with isopropyl acetate 2 times 30ml.The solvent was distilled off under reduced pressure.The resulting generation bold analysis HPLC, the results of the compound (6-1) in a yield of 98%. |
98% | With sodium hypochlorite; In water; at 0℃; for 0.166667h; | 20 g 0.12 mol 3-difluoromethyl-1-methylpyrazole-4-methanone was added to 150 ml of aqueous sodium hypochlorite,The reaction was cooled to 0 C,After 10 minutes of reaction, 45 ml of 10% aqueous sodium sulfite solution was added to the system,Add 30 ml of concentrated hydrochloric acid to the system. After the addition of the reaction after 15 minutes,With concentrated hydrochloric acid to adjust the PH value of 2 to 3,The precipitated white solid was collected.Each time with 16ml of water washed three times,19.8 g of 0.11 mol of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid were obtained as solids,Yield 98%. |
96% | With bromine; sodium hydroxide; In water; at 10 - 15℃; for 3h;Cooling with ice; | In a three-neck round-bottomed flask, 500 g of a 20% NaOH aqueous solution was added.160 grams of bromine were added dropwise on an ice bath.After the dropwise addition was completed, the temperature was maintained at 10 C. 87 g of 3-difluoromethyl-1-methyl-4-acetylpyrazole was dissolved in 90 ml of methanol to prepare an organic solution. The organic solution was then slowly added dropwise to the flask. During the addition, the reaction temperature was maintained at lC ~ 15C. After the addition was completed, the incubation was continued for 3 hours. TLC thin layer chromatography was used to detect complete reaction of the raw materials. The aqueous layer was then extracted with dichloromethane, and the organic layer was recovered as a waste liquid. The extracted aqueous layer was added with a concentration of 31% hydrochloric acid to adjust the pH to 1 to 2, cooled to about 10C, and retained for 0.5 h, suction filtered, and dried to obtain 84 g of the final product in a yield of 96% |
96% | With bromine; sodium hydroxide; In water; at 10 - 15℃; for 3h; | 500 g 20% NaOH water solution is added to a three-neck flask, 160 g bromine is added in the presence of ice bath, at the end of said addition, the said mixture is kept at a temperature below 10 C., subsequently, 87 g 3-difluoromethyl-1-methyl-4-acetyl pyrazol is dissolved in 90 mL methanol, leading to formation of organic solution. The said organic solution is slowly added to the said flask. The temperature of said addition is kept at 1015 C. At the end of said addition, the temperature of said solution is kept and the said reaction continuously takes place for 3 h. TLC is conducted to check the completeness of said reaction. Dichloromethane is added to extract the water phase, and the organic phase is considered as waste solution, wherein the said dichloromethane is recovered from said organic phase. 31% HCl is added to said extracted water phase until the resulting pH value is 12, and then it is cooled to 10 C. and kept at said temperature for 0.5 h, the obtained is vacuum filtered and dried, in this way, 84 g final product is obtained, and the resulting yield is 96%. |
95% | With sodium hypochlorite solution; In water; at 20 - 35℃; for 3h; | A 3 L 2L reactor was charged with 10% sodium hypochlorite aqueous solution 1391 g (1.868 mol) of 1- (3- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) Ethanone 98.6 g (0.566 mol) of The mixture should be heated at 35 or less. After completion of the addition, the mixture was stirred at room temperature for 3 hours, Remove excess sodium hypochlorite. The chloroform layer formed during the reaction was separated and removed, and the aqueous layer was adjusted to pH 1 or lower [0088] By adjusting Methyl-3-difluoromethyl-lH-pyrazole-4-carboxylic acid as crystals. The mixture was stirred at 0 C for 1 hour, filtered and dried to obtain 94.7g (0.538 mol, yield 95%) of difluoromethyl-1H-pyrazole-4-carboxylic acid |
95% | With sodium hypochlorite; In chloroform; at 10 - 15℃; for 3h; | In a three-neck round bottom flask, add 88. 5g of NaClO with a concentration of 10% of available chlorine, and cool the reaction solution to 25C.Slowly add a solution of 100 g of 3-difluoromethyl-1-methyl-4-acetyl-1H-pyrazole (VII) dissolved in 500 ml of chloroform, keeping the reaction temperature at 10 C. to 15 C. and adding dropwise. After incubation for 3 hours, TLC detected the complete reaction of the raw materials. Chloroform was added to extract the aqueous layer. The organic layer was used as the waste solution to recover methylene chloride. The aqueous layer was adjusted with hydrochloric acid with a concentration of 31% to pH=1 to 2, and cooled to about 10C. After incubation for 0.5 hour, the mixture was suction filtered and dried to give 96 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (DFPA) in a yield of 95%. |
95% | With oxygen; acetic acid; at 80℃; for 20h; | Add 25 g (0.14 mol) of 3-trifluoromethyl-1-methyl-4-acetylpyrazole derivative, 80 g of acetic acid,1g manganese nitrate and 1g iron nitrate,Heated up to 80 ,React with oxygen for 20 hours,Evaporate the acetic acid under reduced pressure,Add 80g of water to the residue,Stir to 80 C and cool to 10 C.Filtration and drying gave 3-fluoroalkyl-1-methyl-1H-pyrazole-4-carboxylic acid (DFMPA) (as shown in formula V)24g,The yield was 95%, and the purity by HPLC was 99%. |
95% | With manganese(II) nitrate hexahydrate; oxygen; hexanoic acid; at 100℃; for 8h; | A mixture of compound (a1) (1.0 g), manganese (II) nitrate hexahydrate (0.30 g, 20 mol % relative to compound (a1)) and hexanoic acid (10 g) was heated to 100 C., and mixed gas (oxygen concentration: 21%) of oxygen and nitrogen was flowed into the mixture at 10 ml/min. The reaction progress was monitored by HPLC, and thereby, it was confirmed that the objective compound (b1) was produced. The mixture was heated at 100 C. for 8 hr, and subjected to quantitative analysis by HPLC. It was confirmed thereby that the yield of compound (b1) was 95%. The reaction mixture was cooled to 25 C., and the precipitated solid was collected by filtration. The obtained solid was washed with chloroform and water to give compound (b1) with purity 99% (HPLC analysis). |
91.3% | With sodium hypochlorite; at 10 - 100℃; for 5h; | Adding 72 g above compound of formula (II) to a 2000 ml four orifices reaction bulb equipped with a stirring device and a thermometer, then dropping 500 g 10% sodium hypochlorite solution (0.67 mol) into the reaction bulb, rising the temperature of this reaction system to 100 C., and carrying out reflux reaction for 5 h. After that, cooling the reaction system slowly to 10 C., and crystallizing the resulting product for 2 h. Filtrating the above mixture to obtain crystal, then washing, draining and draying the crystal to obtain 56 g target product. The HPLC-purity of target product is 99.5%, and the yield of this preparation method is 91.3% (the molar yield is calculated with respect to the mole of above compound of formula (II)). Said target product has been analyzed by 1H NMR analysis, elemental analysis and mass spectrometry, which could be determined as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. |
66% | With water; nitric acid; at 100℃; for 6h; | Under an air atmosphere, 69% by mass nitric acid aqueous solution (5.1 g), water (3.9 g), and compound (b1) (1 g) were placed in a flask, and then heated for 6 hours at flask inside temperature of 100 C. After cooling the flask, the content of the flask was analyzed, and as a result, the formation of the compound (a1) was confirmed (yield 66%). After filtering the content of the flask, the compound (a1) obtained as a filtrate is washed with water to obtain a compound (a1). |
With sodium hypochlorite; sodium hydroxide; at 10 - 20℃; for 3h; | 1 eq of 1 -(3 -(difluoromethyl)- i-methyl-i H-pyrazol-4-yl)ethanone is added to 3.3 eq NaOH and 3.3 eq of an 8% sodium hypochlorite solution at 10C. Afteraddition, the reaction mixture is stined for 3 hours at 20C. Dichloromethane, about 20 mL, is added to the mixture and the organic phase discarded. The pH of the aq. phase is brought to 1-2 by addition of 10% HC1. The mixture is stined for 30 minutes at 0C, the precipitate filtered and dried to obtain (3- (difluoromethyl)- i-methyl-i H-pyrazol-4-carboxylic acid. | |
With peracetic acid; acetic acid; at 100℃; | 0.43 g (2.5 mmol) of l-(3-(difluoromethyl)-l -methyl- lH-pyrazol-4- yl)ethanone and 20 g (39 mmol) of peracetic acid (15 wt% in acetic acid) were mixed in a 50 mL three necked flask. The mixture was heated to l00C overnight while being stirred. HPLC showed full conversion of l-(3- (difluoromethyl)- 1 -methyl- 1 H-pyrazol-4-yl)ethanone into 3-(difluoromethyl)- 1 - methyl- 1 H-pyrazole-4-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; sodium hydroxide; In toluene; for 23h;Reflux; | ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate containing 0.2 area%, Purity 96.6 area% of <strong>[141573-95-7]ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate</strong> 10.0 g (0.05 mol), toluene 94 g, water 15.2 g, 25 wt% sodium hydroxide aqueous solution 1.8 g (0.07 mol) were added to the 200ml round-bottomed flask, while stirring it was heated in an oil bath and reacted under reflux for 23 hours. After cooling to room temperature, 15 mass% hydrochloric acid 21.0 g (0.09 mol) was dropped from the dropping funnel. After dropping, after cooling for 1 hour in an ice-water bath, using a 5C filter paper, suction filtered through a Kiriyama funnel, the filtrate was washed with 2 volumes of cold water. The obtained filtrate was dried under reduced pressure at 80 C. for 4 hours and got 8.60 g of crystals. When this crystal was analyzed by HPLC, it was 3- (difluoromethyl) -1-methyl -1H- pyrazole-4-carboxylic acid : 99.2 area %, 5- (difluoromethyl) -1-methyl-1 H-pyrazole-4-carboxylic acid : 0.1 area %. The toluene layer obtained by separating the filtrate into two layers, after concentrated in an evaporator, dried under reduced pressure at 80 C for 4 hours, got 0.02 g of crystals. When this crystal analyzed by HPLC, it was 3- (difluoromethyl) -1-methyl -1H- pyrazole-4-carboxylic acid : 27.2 area %, 5- (difluoromethyl) -1-methyl-1 H-pyrazole-4- carboxylic acid: 15.0 area %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With water; sodium hydroxide; In methanol; at 60℃; for 4h; | A 1 L reaction flask was charged with water (200 mL), methanol (200 mL), sodium hydroxide (10 g, 0.25 mol), and ethylene glycol bis((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)carboxylate) (37.8 g, 0.1 mol). Stirred at 60C for 4 hours. Cooled to room temperature, the methanol was removed by concentration under reduced pressure. Slowly cooled to 0-5C. After stirring for 2 hours, dried to give 3-(difluoromethyl)-1-methyl-1H-pyrazol-4-carboxylic acid as a white solid, 32.4 g, purity 99.2%, yield 92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.3% | With water; sodium hydroxide; In methanol; at 60℃; for 4h; | A 1 L reaction flask was charged with water (300 mL), methanol (300 mL), sodium hydroxide (15 g, 0.38 mol), and hexylene glycol bis((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)carboxylate) (80 g, 0.18 mol). Stirred at 60C for 4 hours. Cooled to room temperature, the methanol was removed by concentration under reduced pressure. Slowly cooled to 0-5C. After stirring for 2 hours, dried to give 3-(difluoromethyl)-1-methyl-1H-pyrazol-4-carboxylic acid as a white solid, 62.5 g, purity 99.8%, yield 96.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.1% | With 1,3-dimethyl-2-imidazolidinone; hydrogen fluoride; triethylamine; at 125 - 155℃;Autoclave; | The 200g of embodiment 16 of the prepared 3 - dichloromethyl - 1H - methyl pyrazole -4 - carboxylic acid methyl ester (GC purity: 97.3%, 0 . 872 muM) into the high-pressure reaction after the cauldron,, slow heating to 125 C -130 C in order to make the 3 - dichloromethyl - 1H - methyl pyrazole -4 - carboxylic acid methyl ester melting. The 5.71g of 1, 3 - dimethyl -2 - imidazolidinone (0.0500 muM), 8.82g triethylamine (0.0872 muM) with 3 - dichloromethyl - 1H - methyl pyrazole -4 - carboxylic acid methyl ester in the high pressure autoclave after mixing, further heated to 130 C -155 C. When the system nylon reach 130 C -155 C when, to maintain the temperature, slowly into the 48.00g of HF (2.399 muM), about 4 - 5 hours drop end, after, in 130 C -155 C insulation 6 - 10 hours. After the reaction, the bleed pressure relief, the nitrogen sweep, tail gas using an absorption. Lowering the temperature to 60 C -80 C, adding 350g xylene and 60g water in order to dilute the reaction liquid, solution is dripped slowly into 145.00g mass concentration of 30% sodium hydroxide aqueous solution (the mass concentration of the refer to sodium hydroxide of the quality of the sodium hydroxide solution the percentage of the total mass of the), in 50 C -70 C insulation stirring 1 hour later, liquid, aqueous phase using the mass concentration is 36% concentrated hydrochloric acid (the mass concentration of the refer to hydrogen chloride of accounting for concentrated hydrochloric acid as a percentage of the total mass of the) to pH=1.0. Lowering the temperature to 10 C -25 C, filtration, vacuum drying, be 138.93g of 3 - difluoromethyl - 1H - methyl pyrazole -4 - carboxylic acid (yield: 90.1%, HPLC purity: 99.6%; isomer 5 - difluoromethyl - 1H - methyl pyrazole -4 - carboxylic acid HPLC purity: _aoltao_ 0.01%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
117.6 g | With 1,3-dimethyl-2-imidazolidinone hexadecahydrofluoric acid salt; at 130 - 155℃; | 200 g of ethyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate prepared according to Example 13 (GC purity: 92.8%, 0.783 mol) and 69.50 gof1,3-dimethyl-2-imidazolidinone hexadecylHydrofluoric acid salts(0.160 mol) was put into a high-pressure reaction vessel, and the temperature was gradually raised to 130 C to 155 C.When the system temperature reaches 130 ~ 155 , to maintain the temperature,And kept at 130 C to 155 C for 7 to 12 hours.After the end of the reaction, the venting pressure, nitrogen purge, the exhaust gas is absorbed by the lye. Cooling to 60 ~ 80 , adding350 g of xylene and 60 g of water to dilute the reaction solution, slowly dropping 125.00 g of sodium hydroxide at a mass concentration of 30%Aqueous solution (the mass concentration refers to the mass of sodium hydroxide as a percentage of the total mass of the aqueous sodium hydroxide solution)After stirring at 70 C for 1 hour, the mixture was separated and the aqueous phase was acidified with a mass concentration of 36% concentrated hydrochloric acid (said mass concentrationRefers to the mass of hydrogen chloride as a percentage of the total mass of concentrated hydrochloric acid) to pH = 1.0. Cooling to 10 ~ 25 , filtration, reallyDried to give 117.60 g of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (yield: 84.5%, HPLC purity: 99.1%;Isomer 5-difluoromethyl-1H-methylpyrazole-4-carboxylic acid HPLC purity: 0.05%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With sodium hydroxide; In water; at 60℃; for 2h; | Example 5 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid To the mixture from example 4, 26.2 g of NaOH in 80 mL water are added. The mixture is heated to 60C for 2 hours. Full conversion is monitored by 1H- NMR. The phases are separated and the aqueous phase extracted with 40 mL toluene. The aqueous phase is acidified with 32 % aq HC1 (66 mL) under vigorous stirring. The suspension which forms is cooled under stirring to 0C, filtered and washed with cold water (3 times 60 mL water). The wet cake is dried under air stream for several hours at room temperature to yield the product. |
With water; methylhydrazine; potassium hydroxide; In acetonitrile; at 20 - 80℃; for 14.5h; | Monomethylhydrazine (40% v/v in water, 1,05 eq), 15 g of the (0351) product of example 7 and 2N aqueous KOH (1,1 eq) are mixed (0352) with 80 mL acetonitrile. The mixture is stirred at room temperature (0353) for 14 hours. The mixture is then heated to 80C for 30 minutes, (0354) cooled to room temperature and the volatiles are removed in vacuo. The organic phase is washed twice with ethyl acetate, and the organic phase discarded. The aqueous phase is acidified with 2N HC1, the resulting suspension is filtered and the solids washed with cold water to yield the product | |
With water; sodium hydroxide; at 50℃; for 1h; | The organic phase of example 3, containing 2,2,2-trichloro-1-(3- (difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethan-1-one, was treated with 15% aq. NaOH (1.2 eq) for 1 hour at 50C. The mixture was cooled to room temperature. The layers were separated, the aqueous layer was washed with dichloromethane, and the aqueous layer was acidified at 0C with 7.1 mL HC1 (37% in water). After 15 minutes at 0C, the mixture was filtered, the solid was rinsed with cold water and dried overnight in vacuum. The overall yield, starting from example 2, was 72.4%. |
With water; sodium hydroxide; at 60℃; for 2h; | To the mixture from example 4, 26.2 g of NaOH in 80 mL water are added. The mixture is heated to 60C for 2 hours. Full conversion is monitored by 1 FI- NMR. The phases are separated and the aqueous phase extracted with 40 mL toluene. The aqueous phase is acidified with 32 % aq HC1 (66 mL) under vigorous stirring. The suspension which forms is cooled under stirring to 0C, filtered and washed with cold water (3 times 60 mL water). The wet cake is dried under air stream for several hours at room temperature to yield the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | A 250 ml single-neck round bottom flask was charged with 56.78 mmol of 3 and 100 ml of dichloromethane. 113.56 mmol of oxalyl chloride and 3 drops of N,N-dimethylformamide were added dropwise to a solution of 3 in dichloromethane, and stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was concentrated under reduced pressure and then diluted with dichloromethane. Under ice bath, it was added dropwise to a 227.12 mmol 25% aqueous ammonia solution in a 250 ml single-neck round bottom flask and stirred overnight. Yielding a white solid 4; yield 98%; The amount of Compound 4 prepared and the volume of the reaction vessel are enlarged or reduced in proportions. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hypochlorite; water; In chloroform; at 24℃; for 4h;Inert atmosphere; | Under nitrogen atmosphere, 11% concentration of aqueous sodium hypochlorite solution (3.1 g) was placed in a flask, and a solution prepared by dissolving compound (b2) (1.0 g) in chloroform (3 ml) was added dropwise to the flask. The reaction solution was stirred at 24 C. for 4 hr, 10% concentration of aqueous sodium sulfite solution (5 ml) was added to the flask, and the aqueous phase was recovered by separation operation. The pH of the obtained aqueous phase was adjusted to 3 or below with sulfuric acid, and the precipitated compound (c1) was collected by filtration to give compound (c1) (yield: 91%). |
With sodium hypochlorite; sodium hydroxide; In water; at 22 - 70℃; for 2h; | 2,2-dichloro- 1- (3-(difluoromethyl) - i-methyl-i H-pyrazol-4-yl)ethanone obtained from example 1 is mixed at 22C with 2 eq NaOH (10% in water) and1.1. eq of a 8% sodium hypochlorite aqueous solution, and then stuffed at 70 C for 2 hours. The reaction solution is quenched with ice water, then saturated sodium sulfite aqueous solution is added. After addition of 3.3 eq 10% HC1, the aqueous phase is extracted twice with isopropyl acetate. The solvent is removed, and 3-difluoromethyl)- i-methyl-i H-pyrazole-4-carboxylic acid is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33%; 33% | Under nitrogen atmosphere, 2.3 g (30.2 mmol) of 1-methyl-1-formylhydrazine was added at 20 C to an ethanol 50 ml solution of 5.0 g (30.1 mmol) of ethyl 4,4-difluoroaceto acetate. Subsequently, the mixture was heated under reflux for 6 hours and then cooled to 20 C. The reaction solution was concentrated with a rotary evaporator. NMR analysis revealed that ethyl 4,4-difluoro-3- (2-formyl-2-methylhydrazono) butanoate (corresponding to compound (11)), ethyl 4,4- difluoro-3- (2-formyl-2-methylhydrazinyl)-2- butenoate (Corresponding to compound (12)) and ethyl 4,4-difluoro-3- (2-formyl-2-methylhydrazinyl)-3-hydroxybutanoate (corresponding to compound (13)) were contained in the concentrate. 50 ml of ethanol was added to the concentrate, then a solution of ethanol 9.8 g of 2.05 g sodium ethoxide was added, then heated under reflux for 2.5 hours and then cooled to room temperature. Ethanol was distilled off and evaporated with a rotary evaporator, and 25 ml of 3 mol / L ammonium chloride aqueous solution, 25 ml of saturated saline and 25 ml of water were added to the obtained residue, and the mixture was extracted with 50 ml of t-butyl methyl ether and liquid-separated. The aqueous phase was further extracted with t-butyl methyl ether, once with 50 ml and then once with 25 ml. The organic phases were combined/mixed, washed with saturated brine 25 ml and then with water 25 ml, then the organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Analysis of the obtained solid by NMR confirmed that 1-methyl-3-difluoromethyl-4-carboxylic acid ethyl ester was obtained in a yield of 33% (based on ethyl 4,4-difluoroaceto acetate) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Repeating the preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid in Example 1 by using 3-(difluoromethyl)-1-methyl-4-(1,3-dioxetan-2-yl)-1H-pyrazole as intermediate. Using 3-(difluoromethyl)-1-methyl-4-(1,3-dioxetan-2-yl)-1-1H-pyrazole as a benchmark to calculate the molar yield of the method, this yield is obtained as 91.0%. The target product has been analyzed by 1H NMR analysis, elemental analysis and mass spectrometry, which could be determined as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.3% | Repeating the preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid in the Example 2 by using 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3-dioxan-2-yl)-1H-pyrazole as intermediate. Using 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3-dioxan-2-yl)-1H-pyrazole s a benchmark to calculate the molar yield of the method, this yield is obtained as 92.3%. The target product has been analyzed by 1H NMR analysis, elemental analysis and mass spectrometry, which could be determined as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.6% | Repeating the preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid in the Example 5 by using 3-(difluoromethyl)-1-methyl-4-(1,3-dioxan-2-yl)-1H-pyrazole as intermediate. Using 3-(difluoromethyl)-1-methyl-4-(1,3-dioxan-2-yl)-1H-pyrazole as a benchmark to calculate the molar yield of the method, this yield is obtained as 91.6%. The target product has been analyzed by 1H NMR analysis, elemental analysis and mass spectrometry, which could be determined as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Repeating the preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid in the Example 2 by using 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3-dioxan-2-yl)-1H-pyrazole as intermediate. Using 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3-dioxan-2-yl)-1H-pyrazole s a benchmark to calculate the molar yield of the method, this yield is obtained as 92.3%. The target product has been analyzed by 1H NMR analysis, elemental analysis and mass spectrometry, which could be determined as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.5% | Equipping a 2000 ml four orifices reaction bulb with a stirring device and a thermometer. Adding 150 g 3-(difluoromethyl)-1-methyl-4-(1,3-dioxolan-2-yl)-1H-pyrazole, 600 g water and 150 g 30% hydrochloric acid (1.23 mol) into the reaction bulb, rising the temperature of this reaction system to 50-60 C. and carrying out hydrolysis reaction for 5 h. Then dropping 150 g 30% hydrogen peroxide (1.32 mol), rising the temperature of this reaction system to 100 C., and carrying out reflux reaction for 5 h. After that, cooling the reaction system slowly to 10 C., and crystallizing the resulting product for 2 h. Filtrating the above mixture to obtain crystal, then washing, draining and draying the crystal to obtain 120 g target product. The HPLC-purity of target product is 99.2%, and the yield of this preparation method is 93.2% (the molar yield is calculated with respect to the mole of above compound of formula (II)). Said target product has been analyzed by 1H NMR analysis, elemental analysis and mass spectrometry, which could be determined as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.3% | Adding 75 g above compound of formula (II), 300 g water and 100 g 30% hydrochloric acid (0.82 mol) to a 2000 ml four orifices reaction bulb equipped with a stirring device and a thermometer, rising the temperature of this reaction system to 50-60 C. and carrying out hydrolysis reaction for 5 h. Then dropping 480 g 10% sodium hypochlorite solution (0.65 mol), rising the temperature of this reaction system to 100 C., and carrying out reflux reaction for 5 h. After that, cooling the reaction system slowly to 10 C., and crystallizing the resulting product for 2 h. Filtrating the mixture to obtain crystal, then washing, draining and draying the crystal to obtain 57.70 g target product. The HPLC-purity of target product is 99.5%, and the yield of this preparation method is 91.3% (the molar yield is calculated with respect to the mole of above compound of formula (II)). Said target product has been analyzed by 1H NMR analysis, elemental analysis and mass spectrometry, which could be determined as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. Elemental analysis result and mass spectrometry result of said target product are as follows: mass spectrometry: m/z: 176.04 (100.0%), 177.04 (7.3%); elemental analysis: C, 40.92; H, 3.43; F, 21.57; N, 15.91; O. 18.17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.2% | Equipping a 2000 ml four orifices reaction bulb with a stirring device and a thermometer. Adding 150 g 3-(difluoromethyl)-1-methyl-4-(1,3-dioxolan-2-yl)-1H-pyrazole, 600 g water and 150 g 30% hydrochloric acid (1.23 mol) into the reaction bulb, rising the temperature of this reaction system to 50-60 C. and carrying out hydrolysis reaction for 5 h. Then dropping 150 g 30% hydrogen peroxide (1.32 mol), rising the temperature of this reaction system to 100 C., and carrying out reflux reaction for 5 h. After that, cooling the reaction system slowly to 10 C., and crystallizing the resulting product for 2 h. Filtrating the above mixture to obtain crystal, then washing, draining and draying the crystal to obtain 120 g target product. The HPLC-purity of target product is 99.2%, and the yield of this preparation method is 93.2% (the molar yield is calculated with respect to the mole of above compound of formula (II)). Said target product has been analyzed by 1H NMR analysis, elemental analysis and mass spectrometry, which could be determined as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.8% | Adding 135 g 3-(difluoromethyl)-1-methyl-4-(2-methyl-1,3-dioxolan-2-yl)-1H-pyrazole, 500 g water and 180 g 30% hydrochloric acid (1.32 mol) to a 3000 ml four orifices reaction bulb equipped with a stirring device and a thermometer, rising the temperature of this reaction system to 50-60 C. and carrying out hydrolysis reaction for 5 h. Dropping 900 g 10% sodium hypochlorite solution (1.21 mol), rising the temperature of this reaction system to 100 C., and carrying out reflux reaction for 5 h. After that, cooling the reaction system slowly down to 10 C., and crystallizing the resulting product for 2 h. Filtrating the above mixture to obtain crystal, then washing, draining and draying the crystal to obtain 118 g target product. The HPLC-purity of target product is 99.3%, and the yield of this preparation method is 91.8%6 (the molar yield is calculated with respect to the mole of above compound of formula (II)). Said target product has been analyzed by 1H NMR analysis, elemental analysis and mass spectrometry, which could be determined as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium iodate; sulfuric acid; iodine; acetic acid; In sulfolane; at 45 - 60℃; for 1.33h; | Sulfuric acid (98 %; 64.37 g) was dropwise added to a mixture of 3-(difluoromethyl)- 1 -methyl- lH-pyrazole (73.5 g, 0.56 mol), Iodine (67.5 g, 0.27 mol), potassium iodate (31 g, 0.14 mol) and acetic acid (816 g) at about 45C in about 20 minutes. The temperature of the reaction mixture was raised to a temperature of about 60C and maintained at the same temperature for an hour. The reaction mixture was quenched with water (500ml) at about 25C to about 30C, the mixture was neutralized with an aqueous solution of sodium bisulfite (lOOml). The mixture was extracted with dichloromethane (200ml). The layers were separated and washed twice with water (500 ml). The organic layers were combined and concentrated to give 3- (difluoromethyl)-4-iodo- 1 -methyl- 1 H-pyrazole. Yield: 90 %; Purity: 96 % |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | General procedure: Under nitrogen atmosphere, carboxylic acid II (3mmol), EDCI (3.3 mmol), HOBT (3.3 mmol)and Et3N (1.8 mmol) were placed in a three-necked flask with 40 mL CH2Cl2, and stirred for 2 hat 0 C; then, compound I (2.4 mmol) was added to the flask and allowed to react for 3 h at 0 C.The reaction was monitored by thin-layer chromatography (TLC) (all reactions could be completed in3 h) and, on completion of the reaction, the mixture was washed with saturated NaHCO3 solutionand water, respectively. Then, it was dried over anhydrous Na2SO4, filtered and evaporated onrotavapor in vacuum. Subsequently, crude products III-1-III-18 were purified by silica gel columnchromatography [V (CH2Cl2): V (EA) = 3:1] and crude products III-19-III-36 were purified by silicagel column chromatography [V (PE): V (EA) = 3:1]. Finally, products were recrystallized with thedichloromethane/petroleum ether to obtain pure target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | General procedure: Under nitrogen atmosphere, carboxylic acid II (3mmol), EDCI (3.3 mmol), HOBT (3.3 mmol)and Et3N (1.8 mmol) were placed in a three-necked flask with 40 mL CH2Cl2, and stirred for 2 hat 0 C; then, compound I (2.4 mmol) was added to the flask and allowed to react for 3 h at 0 C.The reaction was monitored by thin-layer chromatography (TLC) (all reactions could be completed in3 h) and, on completion of the reaction, the mixture was washed with saturated NaHCO3 solutionand water, respectively. Then, it was dried over anhydrous Na2SO4, filtered and evaporated onrotavapor in vacuum. Subsequently, crude products III-1-III-18 were purified by silica gel columnchromatography [V (CH2Cl2): V (EA) = 3:1] and crude products III-19-III-36 were purified by silicagel column chromatography [V (PE): V (EA) = 3:1]. Finally, products were recrystallized with thedichloromethane/petroleum ether to obtain pure target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | General procedure: Under nitrogen atmosphere, carboxylic acid II (3mmol), EDCI (3.3 mmol), HOBT (3.3 mmol)and Et3N (1.8 mmol) were placed in a three-necked flask with 40 mL CH2Cl2, and stirred for 2 hat 0 C; then, compound I (2.4 mmol) was added to the flask and allowed to react for 3 h at 0 C.The reaction was monitored by thin-layer chromatography (TLC) (all reactions could be completed in3 h) and, on completion of the reaction, the mixture was washed with saturated NaHCO3 solutionand water, respectively. Then, it was dried over anhydrous Na2SO4, filtered and evaporated onrotavapor in vacuum. Subsequently, crude products III-1-III-18 were purified by silica gel columnchromatography [V (CH2Cl2): V (EA) = 3:1] and crude products III-19-III-36 were purified by silicagel column chromatography [V (PE): V (EA) = 3:1]. Finally, products were recrystallized with thedichloromethane/petroleum ether to obtain pure target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | General procedure: Under nitrogen atmosphere, carboxylic acid II (3mmol), EDCI (3.3 mmol), HOBT (3.3 mmol)and Et3N (1.8 mmol) were placed in a three-necked flask with 40 mL CH2Cl2, and stirred for 2 hat 0 C; then, compound I (2.4 mmol) was added to the flask and allowed to react for 3 h at 0 C.The reaction was monitored by thin-layer chromatography (TLC) (all reactions could be completed in3 h) and, on completion of the reaction, the mixture was washed with saturated NaHCO3 solutionand water, respectively. Then, it was dried over anhydrous Na2SO4, filtered and evaporated onrotavapor in vacuum. Subsequently, crude products III-1-III-18 were purified by silica gel columnchromatography [V (CH2Cl2): V (EA) = 3:1] and crude products III-19-III-36 were purified by silicagel column chromatography [V (PE): V (EA) = 3:1]. Finally, products were recrystallized with thedichloromethane/petroleum ether to obtain pure target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | General procedure: Under nitrogen atmosphere, carboxylic acid II (3mmol), EDCI (3.3 mmol), HOBT (3.3 mmol)and Et3N (1.8 mmol) were placed in a three-necked flask with 40 mL CH2Cl2, and stirred for 2 hat 0 C; then, compound I (2.4 mmol) was added to the flask and allowed to react for 3 h at 0 C.The reaction was monitored by thin-layer chromatography (TLC) (all reactions could be completed in3 h) and, on completion of the reaction, the mixture was washed with saturated NaHCO3 solutionand water, respectively. Then, it was dried over anhydrous Na2SO4, filtered and evaporated onrotavapor in vacuum. Subsequently, crude products III-1-III-18 were purified by silica gel columnchromatography [V (CH2Cl2): V (EA) = 3:1] and crude products III-19-III-36 were purified by silicagel column chromatography [V (PE): V (EA) = 3:1]. Finally, products were recrystallized with thedichloromethane/petroleum ether to obtain pure target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | General procedure: Under nitrogen atmosphere, carboxylic acid II (3mmol), EDCI (3.3 mmol), HOBT (3.3 mmol)and Et3N (1.8 mmol) were placed in a three-necked flask with 40 mL CH2Cl2, and stirred for 2 hat 0 C; then, compound I (2.4 mmol) was added to the flask and allowed to react for 3 h at 0 C.The reaction was monitored by thin-layer chromatography (TLC) (all reactions could be completed in3 h) and, on completion of the reaction, the mixture was washed with saturated NaHCO3 solutionand water, respectively. Then, it was dried over anhydrous Na2SO4, filtered and evaporated onrotavapor in vacuum. Subsequently, crude products III-1-III-18 were purified by silica gel columnchromatography [V (CH2Cl2): V (EA) = 3:1] and crude products III-19-III-36 were purified by silicagel column chromatography [V (PE): V (EA) = 3:1]. Finally, products were recrystallized with thedichloromethane/petroleum ether to obtain pure target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | General procedure: Under nitrogen atmosphere, carboxylic acid II (3mmol), EDCI (3.3 mmol), HOBT (3.3 mmol)and Et3N (1.8 mmol) were placed in a three-necked flask with 40 mL CH2Cl2, and stirred for 2 hat 0 C; then, compound I (2.4 mmol) was added to the flask and allowed to react for 3 h at 0 C.The reaction was monitored by thin-layer chromatography (TLC) (all reactions could be completed in3 h) and, on completion of the reaction, the mixture was washed with saturated NaHCO3 solutionand water, respectively. Then, it was dried over anhydrous Na2SO4, filtered and evaporated onrotavapor in vacuum. Subsequently, crude products III-1-III-18 were purified by silica gel columnchromatography [V (CH2Cl2): V (EA) = 3:1] and crude products III-19-III-36 were purified by silicagel column chromatography [V (PE): V (EA) = 3:1]. Finally, products were recrystallized with thedichloromethane/petroleum ether to obtain pure target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | General procedure: Under nitrogen atmosphere, carboxylic acid II (3mmol), EDCI (3.3 mmol), HOBT (3.3 mmol)and Et3N (1.8 mmol) were placed in a three-necked flask with 40 mL CH2Cl2, and stirred for 2 hat 0 C; then, compound I (2.4 mmol) was added to the flask and allowed to react for 3 h at 0 C.The reaction was monitored by thin-layer chromatography (TLC) (all reactions could be completed in3 h) and, on completion of the reaction, the mixture was washed with saturated NaHCO3 solutionand water, respectively. Then, it was dried over anhydrous Na2SO4, filtered and evaporated onrotavapor in vacuum. Subsequently, crude products III-1-III-18 were purified by silica gel columnchromatography [V (CH2Cl2): V (EA) = 3:1] and crude products III-19-III-36 were purified by silicagel column chromatography [V (PE): V (EA) = 3:1]. Finally, products were recrystallized with thedichloromethane/petroleum ether to obtain pure target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | General procedure: Under nitrogen atmosphere, carboxylic acid II (3mmol), EDCI (3.3 mmol), HOBT (3.3 mmol)and Et3N (1.8 mmol) were placed in a three-necked flask with 40 mL CH2Cl2, and stirred for 2 hat 0 C; then, compound I (2.4 mmol) was added to the flask and allowed to react for 3 h at 0 C.The reaction was monitored by thin-layer chromatography (TLC) (all reactions could be completed in3 h) and, on completion of the reaction, the mixture was washed with saturated NaHCO3 solutionand water, respectively. Then, it was dried over anhydrous Na2SO4, filtered and evaporated onrotavapor in vacuum. Subsequently, crude products III-1-III-18 were purified by silica gel columnchromatography [V (CH2Cl2): V (EA) = 3:1] and crude products III-19-III-36 were purified by silicagel column chromatography [V (PE): V (EA) = 3:1]. Finally, products were recrystallized with thedichloromethane/petroleum ether to obtain pure target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With copper(I) oxide; tributyl-amine; copper; In sulfolane; at 20 - 150℃; for 6h; | Tributylamine (90gm, 0.48mol) was added to a mixture of 3-(difluoromethyl)-l- methyl-lH-pyrazole-4-carboxylic acid (l70gm, 0.966mol), Cu Powder (l0.8gm, 0.176 mol), and Cu20 (9.67gm, 0.067mol) in sulfolane (252gm, 2.lmol) at ambient temperature. The reaction mixture was stirred at l50C for six hours. After completion of the reaction, the product is distilled off from the reaction under vacuum. Tributylamine was recycled back to the reactor. Yield: 80 % Purity: 95 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With diphenylphosphoranyl azide; N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; at 20 - 90℃; for 4.5h;Inert atmosphere; | Add in a 250 ml double-neck round bottom flask28.3 mmol of pyrazole acid compound I-1,Pyrazole acid is selected from:1-methyl-3-difluoromethyl-4pyrazolecarboxylic acid;Suspended in t-butanol solution,Under nitrogen protection,It was added 36.91 mmol of diphenylphosphoryl azide and 56.78 mmoles N at room temperature, N- diisopropylethylamine,The reaction solution was stirred at room temperature for half an hour.After slowly heating up,Stir at 80 to 90 degrees Celsius for 4 hours.After the reaction is complete,Cool the system to room temperature,Concentrate under reduced pressure to remove excess solvent.The residue is purified by 100-200 mesh silica gel column chromatography to give compound II-1.The eluent is petroleum ether: ethyl acetate at 60-90 degrees Celsius.Depending on the product,Its volume ratio is 10:1-8:1,Yield 76-91% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | To a 200 ml single-neck round bottom flask was added 28.39 mmol 3 dissolved in 40 ml of dichloromethane, and then 31.32 mmol of triethylamine was added. Stir for 10 minutes; Further adding 31.23 mmol of EDCI and catalytic amount of DMAP to the reaction. Stir at room temperature for 30 minutes. Finally, 28.39 mmol of N,O-dimethylhydroxylamine hydrochloride was added to the system. Stir at room temperature overnight, after the reaction is completed, The mixture was suction filtered under reduced pressure and the filtrate was concentrated to remove solvent. It was dissolved in 20 ml of dichloromethane and diluted. Wash once with 30 ml of water, separate the aqueous layer and extract twice with dichloromethane (10 ml × 2). The combined organic layers were washed once with 20 ml of saturated sodium chloride solution. The aqueous layer was separated and extracted twice with dichloromethane (10 mL×2). The combined organic layers were dried over anhydrous sodium sulfate; The filtrate is concentrated to remove the solvent.With petroleum ether / ethyl acetate (2:1, volume / volume) purification by column chromatography to give a white solid 6; yield 91%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.6% | With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine; In dichloromethane; at 20℃; for 21h; | syn-Enriched 5-amino-9-isopropyl-benzonorbornene (49.83g, syn/anti ratio 9:1 ; prepared as described in WO 04/35589 or WO 06/37632) was chromatographed on silica gel (4.7kg) in ethyl acetate-hexane-(1 :6). The first eluting fractions with syn- contents >98% (g.l.c) were combined (5.8Og) and crystallized from hexane to give crystals (4.4Og, 8.8%, m.p. 57-58 0C) with a syn-content of 99.8% (g.l.c). 5-Amino-9-sy/7-isopropyl-benzonorbornene (7.32g, 99.8% syn, prepared as described above) was reacted with 5-difluoromethyl-2-methyl-pyrazole-4-carboxylic acid (8.33g, 1.3 eq., prepared as described in WO 04/35589), bis-(2-oxo-3-oxazolidinyl)-phosphinic acid chloride (12.96g, 1.4 eq.) and triethylamine (9.2g, 2.5 eq.) in dichloromethane (100ml) at room temperature for 21 h to give after aqueous work up with saturated NaHCO3-solution and purification on silica gel in ethyl acetate-hexane-(2:3) a viscous oil. Crystallization from hexane afforded the desired product (12.1g, 92.6%, m.p. 128- 130 0C, 99.2% syn (g.l.c)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.7% | With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine; In dichloromethane; at 20℃; for 3h; | anti-Enriched 5-amino-9-isopropyl-benzonorbornene (42g, syn/anti-ratio 3:7; prepared as described in WO 04/35589 or WO 06/37632) was chromatographed on silica gel (2.1kg ) in ethyl acetate-hexane-(1:7). The last eluting fractions with antf-contents > 97% (1.2 g, g.l.c) were combined and rechromatographed on silica gel (25Og) in ethyl acetate to give 0.72g (1.96%) of a crystalline solid (m.p. 64 0C) with an antf-content of 99.2% (g.l.c).5-Amino-9-anNo.-isopropyl-benzonorbornene (0.72g, 99.2% anti, prepared as described above) was reacted with 5-difluoromethyl-2-methyl-pyrazole-4-carboxylic acid (0.76g, 1.2 eq.)tau bis-(2-oxo-3-oxazolidinyl)-phosphinic acid chloride (1.Og, 1.2 eq.) and triethylamine (0.87g, 2.4 eq.) in dichloromethane (25ml) at room temperature for 3h to give after aqueous work up with saturated NaHCO3-solution and purification on silica gel in ethyl acetate-hexane-(1 :2 ) a viscous oil. Crystallization from hexane afforded the desired product (1.18g, yield: 91.7%, m.p. 140 0C, 99.4% anti (g.l.c)). The crystalline material was analyzed by differential scanning calorimetry and x-ray diffraction and was identified as crystal modification I of anti-3-difluoromethyl-1-methyl-1 H-pyrazole-4- carboxylic acid (9-isopropyl-1 ,2,3,4-tetrahydro-1 ,4-methano-naphthalen-5-yl)-amide no presence of other crystalline forms was detected (see figures 4, 5 and 6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In ethyl acetate; at 80℃; for 3h; | 3-(Difluoromethyl)-1-methyl-pyrazole-4-carboxylic acid (75 mg, 0.43 mmol) and (S)- 6-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine (110 mg, 0.43 mmol) were dissolved in Et3N (0.60 mL, 4.3 mmol). Propylphosphonic anhydride ( 50 wt% in EtOAc, 0.44 mL) was then added and the reaction was heated at 80 C for 3 h. After this time, he reaction was cooled to rt and quenched by addition of MeOH (2 mL). The resulting solid was filtered and dried under vacuum to give the title compound (150 mg, 85%) as a white solid. 1H NMR (400 MHz, MeOD) d ppm 9.01 (s, 1H), 8.30 - 8.38 (m, 1H), 8.18 - 8.26 (m, 1H), 7.92 - 8.05 (m, 2H), 7.05 - 7.41 (m, 2H), 4.02 (s, 3H), 1.85 - 1.94 (m, 3H). MS (ESI): 416.0 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.3% | Stage #1: ethyl 4,4-difluoro-3-oxobutyrate With calcium acetate; orthoformic acid triethyl ester at 100 - 110℃; for 2h; Stage #2: methylhydrazine With sodium hydroxide In 5,5-dimethyl-1,3-cyclohexadiene; water at 10 - 20℃; for 0.5h; | 1-16 Example 9 Add 169.4g (98%, 1.0mol) of ethyl 4,4-difluoroacetoacetate to a 2000ml three-necked bottle equipped with mechanical stirring, condenser, constant pressure dropping funnel and thermometer, and triethyl orthoformate 171.9 (99 %, 1.15mol), xylene 1000mL, calcium acetate 15.8g (0.1mol), start stirring, react at 100 ~ 110 for 2h, then lower the temperature to 10 , add 26.6g of 30% sodium hydroxide aqueous solution Contain NaOH 0.2mol), after completion, add dropwise 115.0g of 40% methyl hydrazine aqueous solution (containing 1.0 mol of methyl hydrazine) and warm to 20 ° C for 0.5 hour. After the reaction, the reaction solution was saponified and acidified to obtain the target product, which was filtered and dried to obtain a light yellow solid product of 147.1g, a yield of 82.5%, and a liquid chromatography quantitative analysis of 98.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.2% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 65 - 75℃; for 1.5h; Inert atmosphere; | 7-9 Example 9: Under the protection of nitrogen, put 12g (0.0585mol) of 3-bromo-1-methyl-1H-pyrazole-4-carboxylic acid, 1,1'-bisdiphenylphosphine ferrocene palladium dichloride into the reaction flask 1.28g (0.0012mol), 5.72g (0.0597mol) of difluoromethylboronic acid and 120mL of 1,4-dioxane, after stirring well, add potassium carbonate aqueous solution (0.142mol), and slowly raise the temperature to 65-75 The reaction was carried out for 1.5 hours, and the raw material was determined to be The system was concentrated under reduced pressure to remove 1,4-dioxane, and ethyl acetate was added to extract impurities. The aqueous phase was adjusted to pH=2-3 with acid, extracted with ethyl acetate, and mercapto silica gel was added to remove palladium. The organic phase was concentrated and replaced with methanol. Then, 65 mL of 35% (v/v) methanol aqueous solution was added for recrystallization to obtain 9.03 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. HPLC: 99.7%, yield 89.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 6h; | 3.3. General Synthetic Procedures for Target Compounds 1-20 General procedure: Intermediate d (10 mmol), EDCI (10 mmol), DMAP (0.1 mmol), and aromatic acid (10 mmol)were dissolved in DCM (CH2Cl2, 30 mL). The mixture was stirred at room temperature for 6 h.The target compounds 1-10 were purified via column chromatography. Similarly, the intermediateb, e, f, and target compounds 11-20 were synthesized by using the same methods. The spectrogram oftarget compounds 1-20 are presented as Supporting Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.5% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 6h; | 3.3. General Synthetic Procedures for Target Compounds 1-20 General procedure: Intermediate d (10 mmol), EDCI (10 mmol), DMAP (0.1 mmol), and aromatic acid (10 mmol)were dissolved in DCM (CH2Cl2, 30 mL). The mixture was stirred at room temperature for 6 h.The target compounds 1-10 were purified via column chromatography. Similarly, the intermediateb, e, f, and target compounds 11-20 were synthesized by using the same methods. The spectrogram oftarget compounds 1-20 are presented as Supporting Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 6h; | General procedure: Intermediate d (10 mmol), EDCI (10 mmol), DMAP (0.1 mmol), and aromatic acid (10 mmol)were dissolved in DCM (CH2Cl2, 30 mL). The mixture was stirred at room temperature for 6 h.The target compounds 1-10 were purified via column chromatography. Similarly, the intermediateb, e, f, and target compounds 11-20 were synthesized by using the same methods. The spectrogram oftarget compounds 1-20 are presented as Supporting Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.4% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 6h; | General procedure: Intermediate d (10 mmol), EDCI (10 mmol), DMAP (0.1 mmol), and aromatic acid (10 mmol)were dissolved in DCM (CH2Cl2, 30 mL). The mixture was stirred at room temperature for 6 h.The target compounds 1-10 were purified via column chromatography. Similarly, the intermediateb, e, f, and target compounds 11-20 were synthesized by using the same methods. The spectrogram oftarget compounds 1-20 are presented as Supporting Information. |
Tags: 176969-34-9 synthesis path| 176969-34-9 SDS| 176969-34-9 COA| 176969-34-9 purity| 176969-34-9 application| 176969-34-9 NMR| 176969-34-9 COA| 176969-34-9 structure
[ 113100-53-1 ]
1-Methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid
Similarity: 0.97
[ 141573-95-7 ]
Ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate
Similarity: 0.92
[ 61859-96-9 ]
Methyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate
Similarity: 0.86
[ 155377-19-8 ]
Ethyl 3-(trifluoromethyl)pyrazole-4-carboxylate
Similarity: 0.84
[ 1202993-11-0 ]
5-Chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid
Similarity: 0.82
[ 113100-53-1 ]
1-Methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid
Similarity: 0.97
[ 78703-53-4 ]
1,3-Dimethyl-1H-pyrazole-4-carboxylic acid
Similarity: 0.83
[ 1202993-11-0 ]
5-Chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid
Similarity: 0.82
[ 40704-11-8 ]
3-Methyl-1H-pyrazole-4-carboxylic acid
Similarity: 0.76
[ 5952-92-1 ]
1-Methyl-1H-pyrazole-4-carboxylic acid
Similarity: 0.72
[ 141573-95-7 ]
Ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate
Similarity: 0.92
[ 1202993-11-0 ]
5-Chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid
Similarity: 0.82
[ 660845-30-7 ]
5-Chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde
Similarity: 0.70
[ 1204298-65-6 ]
5-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid
Similarity: 0.62
[ 1089212-38-3 ]
4-Bromo-3-(difluoromethyl)-1-methyl-1H-pyrazole
Similarity: 0.57
[ 113100-53-1 ]
1-Methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid
Similarity: 0.97
[ 141573-95-7 ]
Ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate
Similarity: 0.92
[ 61859-96-9 ]
Methyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate
Similarity: 0.86
[ 155377-19-8 ]
Ethyl 3-(trifluoromethyl)pyrazole-4-carboxylate
Similarity: 0.84
[ 78703-53-4 ]
1,3-Dimethyl-1H-pyrazole-4-carboxylic acid
Similarity: 0.83
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :