[ CAS No. 741717-63-5 ] {[proInfo.proName]}

Name: 741717-63-5|Ethyl 1-phenyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate|97%
Brand: Ambeed
SKU: A137559
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Quality Control of [ 741717-63-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 741717-63-5 ]

SDS Specification

Alternatived Products of [ 741717-63-5 ]

Product Details of [ 741717-63-5 ]

CAS No. :	741717-63-5	MDL No. :	MFCD10568308
Formula :	C₁₃H₁₁F₃N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RNOJREZLCGQMPX-UHFFFAOYSA-N
M.W :	284.23	Pubchem ID :	11448972
Synonyms :

Calculated chemistry of [ 741717-63-5 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	11
Fraction Csp3 :	0.23
Num. rotatable bonds :	5
Num. H-bond acceptors :	6.0
Num. H-bond donors :	0.0
Molar Refractivity :	64.65
TPSA :	44.12 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.88 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.87
Log Po/w (XLOGP3) :	3.03
Log Po/w (WLOGP) :	4.22
Log Po/w (MLOGP) :	2.81
Log Po/w (SILICOS-IT) :	2.75
Consensus Log Po/w :	3.14

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.59
Solubility :	0.0734 mg/ml ; 0.000258 mol/l
Class :	Soluble
Log S (Ali) :	-3.62
Solubility :	0.0679 mg/ml ; 0.000239 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.29
Solubility :	0.0146 mg/ml ; 0.0000513 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.34

Safety of [ 741717-63-5 ]

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 [ 741717-63-5 ]

* 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 [ 741717-63-5 ]
Downstream synthetic route of [ 741717-63-5 ]

[ 741717-63-5 ] Synthesis Path-Upstream 1~6

1
[ 591-50-4 ]
[ 155377-19-8 ]
[ 741717-63-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	With trans-N,N'-dimethyl-1,2-cyclohexanediamine; copper(l) iodide; potassium carbonate In toluene at 110℃; for 24 h;	A mixture of 3-trifluoromethyl-lH-pyrazole-4-carboxylic acid ethyl ester (2.5 g, 12.0 mmol), copper (I) iodide (0.69 g, 3.6 mmol) and potassium carbonate (3.49 g, 25.3 mmol) in toluene (12 mL) in a round bottom flask was purged with argon. To the reaction mixture was then added iodobenzene (1.61 mL, 14.4 mmol) and racemic trans- N,N'-dimethyl-cyclohexane-l,2-diamine (1.16 mL, 7.2 mmol). The slurry was heated under Ar in an oil bath at HO⁰C for 24 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered over a bed of celite. The organic washings were combined and concentrated to give a crude which was purified by silica gel chromatography (Isco 120 g column, 0 -> 30percent ethyl acetate/hexanes) to give 1- phenyl-3-trifluoromethyl-lH-pyrazole-4-carboxylic acid ethyl ester (2.91 g, 85percent) as an off-white solid. The NMR spectrum obtained on the sample is compatible with its structure.
85%	With potassium carbonate In toluene at 110℃; for 24 h; Inert atmosphere	Part I: Preparation of Preferred Intermediates Preparation of 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid A mixture of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.5 g, 12.0 mmol), copper (I) iodide (0.69 g, 3.6 mmol) and potassium carbonate (3.49 g, 25.3 mmol) in toluene (12 mL) in a round bottom flask was purged with argon. To the reaction mixture was then added iodobenzene (1.61 mL, 14.4 mmol) and racemic trans-N,N'-dimethyl-cyclohexane-1,2-diamine (1.16 mL, 7.2 mmol). The slurry was heated under Ar in an oil bath at 110° C. for 24 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered over a bed of celite. The organic washings were combined and concentrated to give a crude which was purified by silica gel chromatography (Isco 120 g column, 0-->30percent ethyl acetate/hexanes) to give 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.91 g, 85percent) as an off-white solid. The NMR spectrum obtained on the sample is compatible with its structure. A mixture of 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.25 g, 4.4 mmol) and 1N aqueous sodium hydroxide solution (17.3 mL) in methanol (20 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and acidified to pH~1 with 1N aqueous hydrochloric acid. The slurry was extracted with methylene chloride and the combined organic layers were washed with saturated sodium chloride and dried over sodium sulfate. Filtration and concentration gave 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (1 g, 89percent yield) as an off-white solid, which was directly used in the next step without further purification. LCMS calcd for C11H7F3N2O2 (m/e) 256, obsd 255 (M-H).
77%	With potassium carbonate In toluene at 110℃; for 24 h; Sealed tube	According to the procedure of Buchwald et al . (J. Oxg. Chem. 2004, 69, 5578), to a 350 iaL sealed tube flushed vigorously with nitrogen was added ethyl 3- (trifluoromethyl) - lH-pyrazole-4-carboxylate (20.0 g, 96.1 mmol) , 1-iodobenzene (12.9 inL, 115 mmol), potassium carbonate (27.9 g, 202 mmol), copper(I) iodide (0.915 g, 4.80 mmol), and (IS, 2S) -N1,N2- dimethylcyclohexane-l,2-diamine (1.37 g, 9.61 mmol), followed by degassed (argon) toluene (100 mL) . The mixture was stirred for 24 hours at 110⁰C, cooled to room temperature, and filtered through a short silica pad which was thoroughly rinsed with toluene and AcOEt- The filtrate was concentrated in vacuo to give ethyl l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxylate (21 g, 77percent) as a solid: ¹H NMR (400 MHz, CDCl₃) δ 1.39 (t, 3H, J = 7.0 Hz), 4.37 (q, 2H, J = 7.0 Hz), 7.42 (m, IH), 7.52 (m, 2H), 7.72 (m, 2H), 8.48 (m, IH).

77%

With potassium carbonate In toluene at 110℃; for 24 h; sealed tube

According to the procedure of Buchwald et al. [J. Org. Chem. 2004, 6^"S, 5578), to a 350 mL sealed tube flushed vigorously with nitrogen were added ethyl 3- (trifluoromethyl) - lH-pyrazole-4-carboxylate (20.0 g, 96.1 ramol) , 1-iodobenzene s (12.9 ml, 115 mmol) , potassium carbonate (27.9 g, 202 mmol), copper (I) iodide (0.915 g, 4.80 mmol), and (IS, 2S) -N1,N2- dimethylcyclohexane-l,2-diamine (1.37 g, 9.61 mmol), followed by degassed toluene (100 ml) . The mixture was stirred for 24 hours a.t 110⁰C₇ cooled to room temperature, and filtered through o a short silica pad which was rinsed with toluene and EtOAc thoroughly. The filtrate was concentrated in vacuo to give ethyl l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxylate(21 g, 77percent) as a solid: ¹H NMR (400 MHz, CDCl₃) δ 1.39 (t, 3H, J = 7.0 Hz), 4.37 (q, 2H, J = 7.0 Hz), 7.42 (m, IH), 7.52 (m, 2H), 5 7.72 (m, 2H), 8.48 (m, IH).

Reference： [1] Patent: WO2008/141976, 2008, A1, . Location in patent: Page/Page column 55
[2] Patent: US2010/152445, 2010, A1, . Location in patent: Page/Page column 8
[3] Journal of Organic Chemistry, 2004, vol. 69, # 17, p. 5578 - 5587
[4] Patent: WO2008/11130, 2008, A2, . Location in patent: Page/Page column 134-135
[5] Patent: WO2008/11131, 2008, A2, . Location in patent: Page/Page column 270-271
[6] Patent: WO2006/13939, 2006, A1, . Location in patent: Page/Page column 47-48
[7] Patent: US2007/123504, 2007, A1, . Location in patent: Page/Page column 29

2
[ 98-80-6 ]
[ 155377-19-8 ]
[ 741717-63-5 ]

Reference： [1] Molecules, 2012, vol. 17, # 12, p. 14205 - 14218
[2] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 7, p. 2785 - 2795

3
[ 571-55-1 ]
[ 2290-03-1 ]
[ 741717-63-5 ]

Reference： [1] Patent: WO2015/97658, 2015, A1, . Location in patent: Page/Page column 19; 20

4
[ 372-31-6 ]
[ 741717-63-5 ]

Reference： [1] Molecules, 2012, vol. 17, # 12, p. 14205 - 14218

5
[ 571-55-1 ]
[ 741717-63-5 ]

Reference： [1] Molecules, 2012, vol. 17, # 12, p. 14205 - 14218

6
[ 155377-19-8 ]
[ 591-50-4 ]
[ 741717-63-5 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 12, p. 2527 - 2531

[ 741717-63-5 ] Synthesis Path-Downstream 1~23

1
[ 591-50-4 ]
[ 155377-19-8 ]
[ 741717-63-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	With trans-N,N'-dimethyl-1,2-cyclohexanediamine; copper(l) iodide; potassium carbonate; In toluene; at 110℃; for 24h;	A mixture of 3-trifluoromethyl-lH-pyrazole-4-carboxylic acid ethyl ester (2.5 g, 12.0 mmol), copper (I) iodide (0.69 g, 3.6 mmol) and potassium carbonate (3.49 g, 25.3 mmol) in toluene (12 mL) in a round bottom flask was purged with argon. To the reaction mixture was then added iodobenzene (1.61 mL, 14.4 mmol) and racemic trans- N,N'-dimethyl-cyclohexane-l,2-diamine (1.16 mL, 7.2 mmol). The slurry was heated under Ar in an oil bath at HO0C for 24 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered over a bed of celite. The organic washings were combined and concentrated to give a crude which was purified by silica gel chromatography (Isco 120 g column, 0 -> 30% ethyl acetate/hexanes) to give 1- phenyl-3-trifluoromethyl-lH-pyrazole-4-carboxylic acid ethyl ester (2.91 g, 85%) as an off-white solid. The NMR spectrum obtained on the sample is compatible with its structure.
85%	With potassium carbonate;trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; In toluene; at 110℃; for 24h;Inert atmosphere;	Part I: Preparation of Preferred Intermediates Preparation of 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid A mixture of <strong>[155377-19-8]3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester</strong> (2.5 g, 12.0 mmol), copper (I) iodide (0.69 g, 3.6 mmol) and potassium carbonate (3.49 g, 25.3 mmol) in toluene (12 mL) in a round bottom flask was purged with argon. To the reaction mixture was then added iodobenzene (1.61 mL, 14.4 mmol) and racemic trans-N,N'-dimethyl-cyclohexane-1,2-diamine (1.16 mL, 7.2 mmol). The slurry was heated under Ar in an oil bath at 110 C. for 24 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered over a bed of celite. The organic washings were combined and concentrated to give a crude which was purified by silica gel chromatography (Isco 120 g column, 0?30% ethyl acetate/hexanes) to give 1-phenyl-<strong>[155377-19-8]3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester</strong> (2.91 g, 85%) as an off-white solid. The NMR spectrum obtained on the sample is compatible with its structure. A mixture of 1-phenyl-<strong>[155377-19-8]3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester</strong> (1.25 g, 4.4 mmol) and 1N aqueous sodium hydroxide solution (17.3 mL) in methanol (20 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and acidified to pH~1 with 1N aqueous hydrochloric acid. The slurry was extracted with methylene chloride and the combined organic layers were washed with saturated sodium chloride and dried over sodium sulfate. Filtration and concentration gave 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (1 g, 89% yield) as an off-white solid, which was directly used in the next step without further purification. LCMS calcd for C11H7F3N2O2 (m/e) 256, obsd 255 (M-H).
77%	With potassium carbonate;trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; In toluene; at 110℃; for 24h;Sealed tube;	According to the procedure of Buchwald et al . (J. Oxg. Chem. 2004, 69, 5578), to a 350 iaL sealed tube flushed vigorously with nitrogen was added ethyl 3- (trifluoromethyl) - lH-pyrazole-4-carboxylate (20.0 g, 96.1 mmol) , 1-iodobenzene (12.9 inL, 115 mmol), potassium carbonate (27.9 g, 202 mmol), copper(I) iodide (0.915 g, 4.80 mmol), and (IS, 2S) -N1,N2- dimethylcyclohexane-l,2-diamine (1.37 g, 9.61 mmol), followed by degassed (argon) toluene (100 mL) . The mixture was stirred for 24 hours at 1100C, cooled to room temperature, and filtered through a short silica pad which was thoroughly rinsed with toluene and AcOEt- The filtrate was concentrated in vacuo to give ethyl l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxylate (21 g, 77%) as a solid: 1H NMR (400 MHz, CDCl3) delta 1.39 (t, 3H, J = 7.0 Hz), 4.37 (q, 2H, J = 7.0 Hz), 7.42 (m, IH), 7.52 (m, 2H), 7.72 (m, 2H), 8.48 (m, IH).

77%	With potassium carbonate;copper(l) iodide; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In toluene; at 110℃; for 24h;sealed tube;	According to the procedure of Buchwald et al. [J. Org. Chem. 2004, 6"S, 5578), to a 350 mL sealed tube flushed vigorously with nitrogen were added ethyl 3- (trifluoromethyl) - lH-pyrazole-4-carboxylate (20.0 g, 96.1 ramol) , 1-iodobenzene s (12.9 ml, 115 mmol) , potassium carbonate (27.9 g, 202 mmol), copper (I) iodide (0.915 g, 4.80 mmol), and (IS, 2S) -N1,N2- dimethylcyclohexane-l,2-diamine (1.37 g, 9.61 mmol), followed by degassed toluene (100 ml) . The mixture was stirred for 24 hours a.t 1100C7 cooled to room temperature, and filtered through o a short silica pad which was rinsed with toluene and EtOAc thoroughly. The filtrate was concentrated in vacuo to give ethyl l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxylate(21 g, 77%) as a solid: 1H NMR (400 MHz, CDCl3) delta 1.39 (t, 3H, J = 7.0 Hz), 4.37 (q, 2H, J = 7.0 Hz), 7.42 (m, IH), 7.52 (m, 2H), 5 7.72 (m, 2H), 8.48 (m, IH).
	With potassium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine; In toluene; at 110℃; for 24h;	Preparation of 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid A mixture of <strong>[155377-19-8]3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester</strong> (1.25 g, 6.0 mmol), copper (I) iodide (0.342 g, 1.8 mmol) and potassium carbonate (0.58 g, 4.2 mmol) in toluene (6 mL) in a round bottom flask was purged with argon. To the reaction mixture was then added iodobenzene (0.81 mL, 7.2 mmol) and racemic trans-N,N'-dimethyl-cyclohexane-1,2-diamine (0.58 mL, 3.6 mmol). The slurry was heated under Ar in an oil bath at 110 C. for 24 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through a bed of celite. After washing the celite with ethyl acetate, the filtrates were combined and concentrated to give a crude which was purified by silica gel chromatography (Isco 120 g column, 0 to 30% ethyl acetate/hexanes) to give 1-phenyl-<strong>[155377-19-8]3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester</strong> (1.40 g, 82%) as an off-white solid. The NMR spectrum obtained on the sample is compatible with its structure. A mixture of 1-phenyl-<strong>[155377-19-8]3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester</strong> (160 mg, 0.56 mmol) and 1N aqueous sodium hydroxide solution (2.3 mL, 2.3 mmol) in methanol (10 mL) was stirred at room temperature overnight. The reaction mixture was acidified to pH~2 with 1N aqueous hydrochloric acid and concentrated to give 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid as an off-white solid, which was directly used without further purification. LCMS calcd for C11H7F3N2O (m/e) 256, obsd 257 (M+H).

Reference： [1]Patent: WO2008/141976,2008,A1 .Location in patent: Page/Page column 55
[2]Patent: US2010/152445,2010,A1 .Location in patent: Page/Page column 8
[3]Journal of Organic Chemistry,2004,vol. 69,p. 5578 - 5587
[4]Patent: WO2008/11130,2008,A2 .Location in patent: Page/Page column 134-135
[5]Patent: WO2008/11131,2008,A2 .Location in patent: Page/Page column 270-271
[6]Patent: WO2006/13939,2006,A1 .Location in patent: Page/Page column 47-48
[7]Patent: US2007/123504,2007,A1 .Location in patent: Page/Page column 29

2
[ 741717-63-5 ]
[ 107-15-3 ]
[ 1003578-67-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	for 5.0h;Heating / reflux;	To ethyl l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4- carboxylate (20.0 g, 70.36 itimol) was added ethylenediamine (188.2 H-L, 2815 mmol) . The mixture was heated to reflux for 5 hours, cooled to room temperature, and concentrated in vacuo, and the residue was azeotroped several times with toluene to give N- (2-aminoethyl) -l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamide (20.84 g, 99%) as a tan solid: 1H NMR (400 MHz, DMSO-de) delta 1.77 (bs, 2H), 2.68 (t, 2H, J = 6.5 Hz), 3.23 (q, 2H, J = 6.2 Hz), 7.47 (m, IH), 7.60 (m, 2H), 7.83 (m, 2H), 8.28 (m, IH), 9.11 (m, IH); m/z (APCI pos) 299.0 (100%) [M+H] .
99%	for 3.0h;Heating / reflux;	A mixture of ethyl l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxylate (6.60 g, 23.2 mmol) and ethylenediamine (50 ml, 23.2 mmol) was heated at reflux for 3 hours. The mixture was concentrated under reduced pressure to a residue. To the residue was added toluene (50 mL) that was concentrate off, twice. The crude solid was dried under high vacuum overnight to give N- (2-aminoethyl) -l-phenyl-3-(trifluoromethyl) -lH-pyrazole-4-carboxamide (6.9 g, 99% yield) as a light tan solid. The desired product may also be isolated as the hydrochloride salt by dissolving in minimal DCM and adding IN HCl in Et2theta (3-5 molar equivalents) dropwise, filtering the solid and washing with Et2theta. 1H NMR (Free base analog) (DMSO-d6) delta 1.83 (br, 2H), 2.68 (t, J = 6.3 Hz, 2H), 3.21-3.26 (m, 2H), 7.47 (t, J = 7.4 Hz, IH), 7.60 (t, J = 8.0 Hzr 2H), 7.84 (d, J = 7.8 Hz, 2H), 8.29-8.30 (m, IH), 9.11 (s, IH); m/z (APCI pos) 299 (60%) (M+H) .

Reference： [1]Patent: WO2008/11130,2008,A2 .Location in patent: Page/Page column 135-136
[2]Patent: WO2008/11131,2008,A2 .Location in patent: Page/Page column 260-261

3
[ 741717-63-5 ]
[ 875657-54-8 ]

Reference： [1]Patent: WO2006/13939,2006,A1 .Location in patent: Page/Page column 48

4
[ 741717-63-5 ]
[ 142818-01-7 ]

Yield	Reaction Conditions	Operation in experiment
89%	With sodium hydroxide; water; In methanol; at 20.0℃;	A mixture of l-phenyl-3-trifluoromethyl-lH-pyrazole-4-carboxylic acid ethyl ester (1.25 g, 4.4 mmol) and IN aqueous sodium hydroxide solution (17.3 mL) in methanol (20 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and acidified to pH ~ 1 with IN aqueous hydrochloric acid. The slurry was extracted with methylene chloride and the combined organic layers were washed with saturated sodium chloride and dried over sodium sulfate. Filtration and concentration gave l-phenyl-3- trifluoromethyl-lH-pyrazole-4-carboxylic acid (1 g, 89% yield) as an off-white solid, which was directly used in the next step without further purification. LCMS calcd forCl 1H7F3N2O2 (m/e) 256, obsd 255 (M-H).
89%		Part I: Preparation of Preferred Intermediates Preparation of 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid A mixture of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.5 g, 12.0 mmol), copper (I) iodide (0.69 g, 3.6 mmol) and potassium carbonate (3.49 g, 25.3 mmol) in toluene (12 mL) in a round bottom flask was purged with argon. To the reaction mixture was then added iodobenzene (1.61 mL, 14.4 mmol) and racemic trans-N,N'-dimethyl-cyclohexane-1,2-diamine (1.16 mL, 7.2 mmol). The slurry was heated under Ar in an oil bath at 110 C. for 24 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered over a bed of celite. The organic washings were combined and concentrated to give a crude which was purified by silica gel chromatography (Isco 120 g column, 0?30% ethyl acetate/hexanes) to give <strong>[741717-63-5]1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester</strong> (2.91 g, 85%) as an off-white solid. The NMR spectrum obtained on the sample is compatible with its structure. A mixture of <strong>[741717-63-5]1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester</strong> (1.25 g, 4.4 mmol) and 1N aqueous sodium hydroxide solution (17.3 mL) in methanol (20 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and acidified to pH~1 with 1N aqueous hydrochloric acid. The slurry was extracted with methylene chloride and the combined organic layers were washed with saturated sodium chloride and dried over sodium sulfate. Filtration and concentration gave 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (1 g, 89% yield) as an off-white solid, which was directly used in the next step without further purification. LCMS calcd for C11H7F3N2O2 (m/e) 256, obsd 255 (M-H).
78%		To a solution of ethyl l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxylate (0.800 g, 2.81 mmol) in EtOH (20 mL) and THF (5 mL) was added 2M aqueous sodium hydroxide (1.69 mL, 8.44 mmol) . The mixture was heated to reflux until TLC indicated completion, cooled to room temperature, and concentrated in vacuo. The residue was dissolved in water and washed with ether. The aqueous layer was then adjusted to pH~4 with 10% HCl. The solid was collected by filtration and dried under vacuum to give l-phenyl-3- (trifluoromethyl) -lH-pyrazole- 4-carboxylic acid (0.560 g, 78%) as a white powder: 1H NMR (400 MHz, DMSO-d6) delta 7.47 (m, IH), 7.58 (m, 2H), 7.94 (m, 2H), 9.24 (bs, IH); m/z (APCI neg) 254.9 (100%) [M-H] .

78%		To a solution of ethyl l-phenyl-3- {trifluoromethyl) -IH- pyrazole-4-carboxylate (0.800 g, 2.81 mmol) in EtOH (20 ml) and 0 THF (5 ml) was added 2N NaOH (1.69 ml, 8.44 mmol). The mixture was refluxed until TLC indicated completion, cooled to room temperature, and concentrated in vacuo. The residue was dissolved in water and washed with ether. The aqueous layer was then adjusted to pH ~4 with 10% HCl. The solid was 5 collected by filtration and dried under vacuum to give 1- phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxylic acid (0.560 g, 78%) as a powder: 1H NMR (400 MHz7 DMSO-d6) delta 7.47 (m, IH), 7.58 (m, 2H), 7.94 (m, 2H), 9.24 (br, IH); m/z 254.9 (APCI neg) (100%) (M-H) . 0
		A mixture of <strong>[741717-63-5]1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester</strong> (160 mg, 0.56 mmol) and 1N aqueous sodium hydroxide solution (2.3 mL, 2.3 mmol) in methanol (10 mL) was stirred at room temperature overnight. The reaction mixture was acidified to pH2 with 1N aqueous hydrochloric acid and concentrated to give 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid as an off-white solid, which was directly used without further purification. LCMS calcd for C11H7F3N2O (m/e) 256, obsd 257 (M+H).

Reference： [1]Molecules,2012,vol. 17,p. 14205 - 14218
[2]Patent: WO2008/141976,2008,A1 .Location in patent: Page/Page column 55
[3]Patent: US2010/152445,2010,A1 .Location in patent: Page/Page column 8
[4]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 2785 - 2795
[5]Patent: WO2008/11130,2008,A2 .Location in patent: Page/Page column 134-135
[6]Patent: WO2008/11131,2008,A2 .Location in patent: Page/Page column 270-271
[7]Patent: US2007/123504,2007,A1 .Location in patent: Page/Page column 29
[8]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 2527 - 2531

5
[ 98-80-6 ]
[ 155377-19-8 ]
[ 741717-63-5 ]

Reference： [1]Molecules,2012,vol. 17,p. 14205 - 14218
[2]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 2785 - 2795

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[ 372-31-6 ]
[ 741717-63-5 ]