[ CAS No. 1204298-65-6 ] {[proInfo.proName]}

Name: 1204298-65-6|5-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid|98%
Brand: Ambeed
SKU: A292176
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CAS No. 1204298-65-6, is a pyrazoles compound, with a molecular weight of 176.12, molecular formula C₆H₆F₂N₂O₂, Ambeed provides reports for batches of (such as NMR, HPLC/GC).

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Quality Control of [ 1204298-65-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1204298-65-6 ]

Product Details of [ 1204298-65-6 ]

CAS No. :	1204298-65-6	MDL No. :	MFCD12827721
Formula :	C₆H₆F₂N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CTTXMUZEFPPHGD-UHFFFAOYSA-N
M.W :	176.12	Pubchem ID :	50989016
Synonyms :

Calculated chemistry of [ 1204298-65-6 ]

Physicochemical Properties

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 Å²

Pharmacokinetics

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

Lipophilicity

Log Po/w (iLOGP) :	1.05
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 :	0.85

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.85

Water Solubility

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

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.6

Safety of [ 1204298-65-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1204298-65-6 ]

* 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.

Upstream synthesis route of [ 1204298-65-6 ]
Downstream synthetic route of [ 1204298-65-6 ]

[ 1204298-65-6 ] Synthesis Path-Upstream 1~6

1
[ 60-34-4 ]
[ 1204298-65-6 ]

Yield	Reaction Conditions	Operation in experiment
67.1%	Stage #1: at -15 - -5℃; for 19.5 h; Stage #2: With sodium hydroxide In ethanol; water at 50℃; for 7 h; Stage #3: With hydrogenchloride In water	Zu einer Losung aus 2394 g (10.35 mol) ETHYL-2- (DIFLUORACETYL)-3-ETHOXYACRYLAT in 5.4 1 Ethanol tropft man bei-15oC bis-5oC innerhalb von 3.5 h eine Losung von 527.8 g (11.45 mol) Methyl- hydrazin in 0. 71 Ethanol und ruhrt fur 16 Stunden nach. Anschliesend gibt man 560 g (14 mol) Natri- umhydroxid und 3.5 1 Wasser zu und ruhrt 7 h bei 50oC. Das Reaktionsgemisch wird abgekuhlt und unter vermindertem Druck eingeengt. Der Ruckstand wird in 6 1 Wasser und 7 kg Eis aufgenommen und mit Dichlormethan gewaschen (einmal 3 1, einmal 2 1). Die eiskalte Wasserphase wird mit kon- zentrierter Salzsaure auf pH 2 eingestellt, das ausgefallene Produkt abgesaugt und im Vakuum- schrank getrocknet. Das Rohprodukt wird in 8 1 Isopropanol (heis) unter Ruckfluss gelost, anschlie- send abgekuhlt, 30 min bei 0oC bis 5oC geruhrt, abgesaugt, mit 1.4 1 Isopropanol (5oC) NACHGE- waschen und bei 40oC im Vakuumschrank getrocknet. Man erhalt 1226. 4 G (99. 8percent IG, 67. 1 percent der Theorie) an L-METHYL-5-DIFLUORMETHYL-PYRAZOL-4- carbonsaure [Log P (pH 2. 3) = 0.52].

Reference： [1] Patent: WO2005/3077, 2005, A1, . Location in patent: Page 13

2
[ 53927-12-1 ]
[ 1550-50-1 ]
[ 60-34-4 ]
[ 176969-34-9 ]
[ 1204298-65-6 ]

Reference： [1] Patent: US2010/184994, 2010, A1, . Location in patent: Page/Page column 9

3
[ 851725-87-6 ]
[ 176969-34-9 ]
[ 1204298-65-6 ]

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).

Reference： [1] Patent: CN106467492, 2017, A, . Location in patent: Paragraph 0224; 0225; 0226; 0227; 0228; 0229; 0230-0235

4
[ 141573-95-7 ]
[ 176969-34-9 ]
[ 1204298-65-6 ]

Reference： [1] Patent: JP5830957, 2015, B2, . Location in patent: Paragraph 0040

5
[ 1086400-66-9 ]
[ 60-34-4 ]
[ 176969-34-9 ]
[ 1204298-65-6 ]

Reference： [1] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5
[2] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5
[3] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5
[4] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5
[5] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5
[6] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5-6
[7] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5
[8] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5-6
[9] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5

6
[ 1550-50-1 ]
[ 34846-90-7 ]
[ 60-34-4 ]
[ 176969-34-9 ]
[ 1204298-65-6 ]

Reference： [1] Patent: US2010/184994, 2010, A1, . Location in patent: Page/Page column 9

[ 1204298-65-6 ] Synthesis Path-Downstream 1~11

1
(E/Z)-ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate [ No CAS ]
[ 60-34-4 ]
[ 1204298-65-6 ]

Yield	Reaction Conditions	Operation in experiment
67.1%		Zu einer Losung aus 2394 g (10.35 mol) ETHYL-2- (DIFLUORACETYL)-3-ETHOXYACRYLAT in 5.4 1 Ethanol tropft man bei-15oC bis-5oC innerhalb von 3.5 h eine Losung von 527.8 g (11.45 mol) Methyl- hydrazin in 0. 71 Ethanol und ruhrt fur 16 Stunden nach. Anschliesend gibt man 560 g (14 mol) Natri- umhydroxid und 3.5 1 Wasser zu und ruhrt 7 h bei 50oC. Das Reaktionsgemisch wird abgekuhlt und unter vermindertem Druck eingeengt. Der Ruckstand wird in 6 1 Wasser und 7 kg Eis aufgenommen und mit Dichlormethan gewaschen (einmal 3 1, einmal 2 1). Die eiskalte Wasserphase wird mit kon- zentrierter Salzsaure auf pH 2 eingestellt, das ausgefallene Produkt abgesaugt und im Vakuum- schrank getrocknet. Das Rohprodukt wird in 8 1 Isopropanol (heis) unter Ruckfluss gelost, anschlie- send abgekuhlt, 30 min bei 0oC bis 5oC geruhrt, abgesaugt, mit 1.4 1 Isopropanol (5oC) NACHGE- waschen und bei 40oC im Vakuumschrank getrocknet. Man erhalt 1226. 4 G (99. 8% IG, 67. 1 % der Theorie) an L-METHYL-5-DIFLUORMETHYL-PYRAZOL-4- carbonsaure [Log P (pH 2. 3) = 0.52].

Reference： [1]Patent: WO2005/3077,2005,A1 .Location in patent: Page 13

2
[ 1086400-66-9 ]
[ 60-34-4 ]
[ 176969-34-9 ]
[ 1204298-65-6 ]

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.

Reference： [1]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5
[2]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5
[3]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5
[4]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5
[5]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5
[6]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5-6
[7]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5
[8]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5-6
[9]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5

3
[ 53927-12-1 ]
[ 1550-50-1 ]
[ 60-34-4 ]
[ 176969-34-9 ]
[ 1204298-65-6 ]

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%.

Reference： [1]Patent: US2010/184994,2010,A1 .Location in patent: Page/Page column 9

4
[ 1550-50-1 ]
[ 34846-90-7 ]
[ 60-34-4 ]
[ 176969-34-9 ]
[ 1204298-65-6 ]

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.

Reference： [1]Patent: US2010/184994,2010,A1 .Location in patent: Page/Page column 9

5
ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate [ No CAS ]
[ 141573-95-7 ]
[ 176969-34-9 ]
[ 1204298-65-6 ]

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 %.

Reference： [1]Patent: JP5830957,2015,B2 .Location in patent: Paragraph 0040

6
methyl-3-(dichloromethyl)-1-methyl-1H-pyrazole-4-carboxylate [ No CAS ]
[ 176969-34-9 ]
[ 1204298-65-6 ]

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%).

Reference： [1]Patent: CN106467492,2017,A .Location in patent: Paragraph 0185; 0186; 0187-0214; 00258; 0259; 0260-0263

7
[ 851725-87-6 ]
[ 176969-34-9 ]
[ 1204298-65-6 ]

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%).

Reference： [1]Patent: CN106467492,2017,A .Location in patent: Paragraph 0224; 0225; 0226; 0227; 0228; 0229; 0230-0235

8
[ 1204298-65-6 ]
6-(2-amino-5-chlorothiazol-4-yl)-3,4-dihydroquinolin-2(1H)-one [ No CAS ]
5-(difluoromethyl)-1-methyl-N-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)-1H-pyrazole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With pyridine; propylphosphonic anhydride; In ethyl acetate; acetonitrile; at 100℃; for 16h;Sealed tube;	To a suspension of 6-(2-amino-5-chlorothiazol-4-yl)-3,4-dihydroquinolin-2(1H)-one (0.100 g, 0.41 mmol), <strong>[1204298-65-6]5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid</strong> (0.080 g, 0.45 mmol), pyridine (0.15 mL, 1.83 mmol) in acetonitrile (4 mL) in a sealed tube was added propylphosphonic anhydride solution (50 wt % in ethyl acetate, 0.61 mL, 1.02 mmol). The sealed tube was heated to 100 C. for 16 h. After cooling, the precipitate was collected by filtration and washed with cold 1:1 acetonitrile/water to give 5-(difluoromethyl)-1-methyl-N-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)thiazol-2-yl)-1H-pyrazole-4-carboxamide (0.119 g, 72%). 1H NMR (400 MHz, DMSO-d): delta 12.74 (bs, 1H), 10.19 (s, 1H), 8.45 (s, 1H), 7.74 (m, 1H), 7.69 (dd, 1H, J=8.4, 2.0 Hz), 7.56 (t, JHF=54 Hz, 1H), 7.53 (s, 1H), 6.90 (d, 1H, J=8.0 Hz), delta, 4.04 (s, 3H), 2.93 (t, 2H, J=7.2 Hz), 2.48 (partial masked under d-DMSO, m, 2H); MS (ESI): Calcd. for C18H15F2N5O2S: 403, found 404 (M+1)+.

Reference： [1]Patent: US2018/201610,2018,A1 .Location in patent: Paragraph 0355; 0356

9
5-(difluoromethyl)-4-(furan-2-yl)-1-methyl-1H-pyrazole [ No CAS ]
[ 1204298-65-6 ]

Reference： [1]Journal of Organic Chemistry,2019,vol. 84,p. 7148 - 7158

10
[ 1204298-65-6 ]
5-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro-[1,1′-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2019,vol. 84,p. 7148 - 7158

11
[ 1204298-65-6 ]
C₆H₅ClF₂N₂O [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2019,vol. 84,p. 7148 - 7158

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[ 1204298-65-6 ] Synthesis Path-Upstream 1~6

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Fluorinated Building Blocks

Carboxylic Acids

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Pyrazoles

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