31686-94-9|Ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate| Ambeed

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Quality Control of [ 31686-94-9 ] Purity: 98% SDS Specification

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Product Details of [ 31686-94-9 ]

CAS No. :	31686-94-9
Formula :	C₁₂H₁₁FO₄
M.W :	238.21
SMILES Code :	CCOC(=O)C(=O)CC(=O)C1=CC=C(F)C=C1
MDL No. :	MFCD02672449
InChI Key :	LVLZSYCLOPEBSR-UHFFFAOYSA-N
Pubchem ID :	596593

Safety of [ 31686-94-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 31686-94-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	17
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	6
Num. H-bond acceptors	5.0
Num. H-bond donors	0.0
Molar Refractivity	57.31
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	60.44 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.75
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.98
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.95
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.36
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.69
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.95

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.43
Solubility	0.886 mg/ml ; 0.00372 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.88
Solubility	0.318 mg/ml ; 0.00133 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.47
Solubility	0.0813 mg/ml ; 0.000341 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	Yes
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.35 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	2.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.82

Application In Synthesis of [ 31686-94-9 ]

* 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.

Downstream synthetic route of [ 31686-94-9 ]

[ 31686-94-9 ] Synthesis Path-Downstream 1~35

1
[ 403-42-9 ]
[ 95-92-1 ]
[ 31686-94-9 ]

Yield	Reaction Conditions	Operation in experiment
96%	With ethanol; sodium; at 10℃;	Synthesis of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate:In a 2L round bottom flask equipped with a reflux condenser and a CaCl2 drying tube metallic sodium (49.9 g, 2.17 mol, 3.0 equiv.) was dissolved in ethanol (1.0 L) carefully. The resulting sodium ethylate solution was cooled to about 10 C then the mixture of l -(4-fluorophenyl)ethan-l-one (100.0 g, 0.72 mol) and diethyl oxalate (2) (295 mL, 2.17 mol, 3.0 equiv.) was poured slowly into it. The reaction mixture was stirred for about 15 minutes, and then was allowed to stand in a refrigerator overnight. The reaction mixture was poured into a mixture of cone. HC1 solution (300 mL) and ice (c.a. 1 kg). The resulting precipitate was filtered off and washed with plenty of water, finally dried in a vacuum desiccator over P2O5/KOH. Yield: 165.5 g (3) (96%) as a light yellow .powder.
81%	With sodium ethanolate; In ethanol; at 0 - 20℃; for 5h;	sodium ethoxide (20 mL, 2.00 eq.) was added to a solution of 1-(4-fluorophenyl)ethan-1-one (5 g, 36.20 mmol, 1.00 eq.) and diethyl oxalate (5.29 g, 36.20 mmol, 1.00 eq.) in ethanol (50 mL) at 0C. The resulting solution was stirred for 5 hours at room temperature, diluted with 500 mL of water and thesolids were collected by filtration. This resulted in 7 g (8 1%) of ethyl 4-(4-fluorophenyl)-2,4- dioxobutanoate as a yellow solid.
81%	With sodium ethanolate; In ethanol; at 0 - 20℃; for 5h;	sodium ethoxide (20 mL, 2.00 eq.) was added to a solution of l-(4-fluorophenyl)ethan-l-one (5 g, 36.20 mmol, 1.00 eq.) and diethyl oxalate (5.29 g, 36.20 mmol, 1.00 eq.) in ethanol (50 mL) at 0C. The resulting solution was stirred for 5 hours at room temperature, diluted with 500 mL of water and the solids were collected by filtration. This resulted in 7 g (81%) of ethyl 4-(4-fluorophenyl)-2,4- dioxobutanoate as a yellow solid.

70%		To a solution of sodium ethoxide (351 mL, 21% in ethanol, 1629 mmol) was added 1-(4-fluorophenyl) ethanone (150 g, 1086 mmol) in ethanol (100 mL) at 0 C. under a nitrogen atmosphere and the resulting reaction mixture was stirred at RT for 10 min Diethyl oxalate (156 mL, 1140 mmol) in ethanol (100 mL) was added and reaction was allowed to stir at RT for 12 h. Reaction mixture was cooled to 0 C. and acidified with 1.5 N HCl and the solid was filtered and the filtrate was diluted with water and extracted with DCM (3*750 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to afford Intermediate 1A (180 g, 70%) which was taken to next step without further purification. MS(ES): m/z=237 [M-H]+; 1H NMR (300 MHz, CDCl3) delta ppm 15.2 (bs, 1H), 8.00-8.09 (m, 2H), 7.15-7.25 (m, 2H), 7.05 (s, 1H), 4.42 (q, J=7.15 Hz, 2H), 1.43 (t, J=7.15 Hz, 3H).
70%		To a solution of sodium ethoxide (351 mL, 21% in ethanol, 1629 mmol) was added l-(4-fluorophenyl) ethanone (150 g, 1086 mmol) in ethanol (100 mL) at 0 C under a nitrogen atmosphere and stirred at RT for 10 min. Diethyl oxalate (156 mL, 1140 mmol) in ethanol (100 mL) was added and reaction was allowed to stir at RT for 12 h. The reaction mixture was cooled to 0 C and acidified with 1.5 N HCl and the solid was filtered and the filtrate was diluted with water and extracted with DCM (3 x 750 mL). The combined organic layer was washed with brine, dried over Na2S04, filtered and concentrated to afford Intermediate 1A (180 g, 70%), which was taken to next step without further purification. MS(ES): m/z = 237 [M-H]+; 1H NMR (300 MHz, CDC13) delta ppm 15.2 (bs, 1H), 8.00 - 8.09 (m, 2H), 7.15 - 7.25 (m, 2H), 7.05 (s, 1H), 4.42 (q, J = 7.15 Hz, 2H), 1.43 (t, J= 7.15 Hz, 3H)
54%		To a solution of diisopropyl amine (6.2mL, 44mmol) in THF (44mL) at 0C was added n-BuLi (16.2mL, 40.5mmol). The cloudy yellow solution was stirred at 0C for 30 min., then cooled to -78C. 4?-fluoroacetophenone (3.2mL, 26 mmol) was added slowly along the sides of the flask and was stirred for 15 min. Diethyl oxalate (7.9mL, 58 mmol) was added and the reaction stirred at -78C for 1 hour. The mixture was warmed to room temperature and stirred for 20 min and the reaction was quenched by the addition of 1M HCl. The organic solvent was removed by rotary evaporation. The aqueous phase was extracted with EtOAc (3× 75mL) and the combined organic layers were washed with 1M HCl (25mL), saturated aqueuos NaHCO3 (25mL), and brine (25mL). The organic phase was dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography and recrystallized from EtOH to obtain 2b (3.38 g, 54% yield) as a yellow solid. 1HNMR (500 MHz, CDCl3) delta 15.83 - 15.03 (m, 1H), 8.42 - 8.09 (m, 2H), 7.50 (s, 1H), 7.42 (t, J= 8.5Hz, 2H), 4.64 (q, J= 7.1Hz, 2H), 1.65(t, J= 7.2Hz, 3H). 13C NMR (125 MHz, CDCl3) delta 189.86, 169.33, 166.36 (d, J= 256.5Hz), 162.27, 131.50 (d, J= 2.5Hz), 130.72 (d,J= 9.5Hz) , 116.3 (d, J= 22.0Hz) , 97.96, 62.83, 14.25.
54%		To a solution of diisopropyl amine (6.2 mL, 44 mmol) in THF (44 mL) at 0 C was added n-BuLi (16.2 mL, 40.5 mmol). The cloudy yellow solution was stirred at 0 C for 30 min., then cooled to -78 C. 4'-fluoroacetophenone (3.2 mL, 26 mmol) was added slowly along the sides of the flask and was stirred for 15 min. Diethyl oxalate (7.9 mL, 58 mmol) was added and the reaction stirred at -78 C for 1 hour. The mixture was warmed to room temperature and stirred for 20 min and the reaction was quenched by the addition of 1M HC1. The organic solvent was removed by rotary evaporation. The aqueous phase was extracted with EtOAc (3 x 75 mL) and the combined organic layers were washed with 1M HC1 (25 mL), saturated aqueuos NaHC03 (25 mL), and brine (25 mL). The organic phase was dried over Na2S04, filtered, and concentrated. The crude material was purified by flash column chromatography and recrystallized from EtOH to obtain 2b (3.38 g, 54 % yield) as a yellow solid. NMR (500 MHz, CDCl3) d 15.83 - 15.03 (m, 1H), 8.42 - 8.09 (m, 2H), 7.50 (s, 1H), 7.42 (t, J = 8.5 Hz, 2H), 4.64 (q, J = 7.1 Hz, 2H), 1.65 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) d 189.86, 169.33, 166.36 (d, J = 256.5 Hz), 162.27, 131.50 (d, J = 2.5 Hz), 130.72 (d, J = 9.5 Hz), 116.3 (d, J = 22.0 Hz), 97.96, 62.83, 14.25.
		Example 54 Ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate To a solution of sodium metal (1.03 g, 45.0 mmol) in ethanol (100 mL) were slowly added drops of 1-(4-fluorophenyl)ethanone (4.50 mL, 36.9 mmol) at 0 C. The solution was stirred for 30 min, and then slowly added drops of diethyl oxalate (5.50 mL, 40.5 mmol) at the same temperature. Following stirring overnight at room temperature, the progression of the reaction was monitored by TLC (Hexane:EtOAc=4:1). When the reaction was completed, the reaction mixture was concentrated in vacuo. To the concentrate, 6M HCl was added dropwise at 0 C., followed by extraction with dichloromethane and water. The organic layer thus formed was dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound without further purification (9.07 g, quant., yellow solid). 1H NMR (300 MHz, CDCl3) delta 8.09-8.04 (m, 2H), 7.24-7.20 (m, 2H), 7.07 (s, 1H), 4.44 (q, J=7.2 Hz, 2H), 1.45 (t, J=7.2 Hz, 3H)
		To a stirred solution of NaH (60%) (15.0 g, 361mmol), in toluene (400mL) at 0 C, was added 4-fluoro acetophenone (25.0 g, 181mmol) drop wise at 0 C. The reaction mixture was then stirred at 0 C for 30 minutes. Diethyl oxalate (37mL, 271mmol) was added drop wise at 0 C. The reaction mixture was stirred at 25 C for 2h. The reaction mixture was diluted with water (lOOOmL) and extracted in ethyl acetate (250mL x 3). The organic layer was washed with brine (250mL), dried over anhydrous sodium sulphate and distilled off to obtain crude ethyl 4-(4-fluorophenyl)-2,4- dioxobutanoate (44.0 g) as a liquid. This was carry forward to next step without further purification. (238.96 [M+H]).
	With sodium ethanolate; In ethanol; at 70℃; for 5h;	General procedure: 0.1 mol (1 eq) of substituted acetophenone and 0.2 mol (29.2 g, 2 eq) of diethyl oxalate were weighed into a 250 ml three-Add 100ml absolute absolute ethanol,Slowly drop the newly prepared ethanol solution of sodium ethoxide,Plus,The temperature was raised to 70 C for 5 hours,TLC detection,No raw materials to replace acetophenone,Reaction finished,The system is reddish brown.Stop heating,The solvent was distilled off under reduced pressure,Dark red brown sticky material,With about 100 ml of water transferred to 200 ml of ice water,With concentrated hydrochloric acid 8ml adjusted to pH 1,Stirring for 30min, filtering,The filter cake was washed with ice ethanol.; The substituted acetophenones are p-fluoroacetophenone, p-chloroacetophenone, p-bromoacetophenone, p-methylacetophenone and p-trifluoro(2a-2e) are ethyl 4- (4-fluorophenyl) -2,4-dioxobutyrate, 4- (4- (4-fluorophenyl) Chlorophenyl) -2,4-dioxobutyrate, ethyl 4- (4-bromophenyl) -2,4-dioxobutyrate, 4- (4-methylphenyl) 2,4-dioxobutyrate, ethyl 4- (4-trifluoromethylphenyl) -2,4-dioxobutyrate, as follows:
	With sodium hydride; In toluene; mineral oil; at 50℃; for 1.5h;Reflux;	General procedure: To a stirred solution of appropriate methyl ketone (0.1 mol) in dry toluene (200 mL)was added a suspension of NaH in mineral oil (60%; 0.2 mol) in portions and the mixture was warmed to50 C. At this temperature a solution of diethyl oxalate (0.15 mol) in dry toluene (60 mL) was addeddropwise under stirring. The reaction mixture was refluxed for 1.5 h. Upon cooling to room temperatureacetic acid (0.25 mol) was added dropwise. The reaction mixture was washed with water (200 mL), organicphase was dried over MgSO4 and evaporated to dryness. The obtained crude diketone was dissolved inethanol (250 mL), hydrazine dihydrochloride (0.11 mol) was added and the mixture was refluxed for 3 h.After evaporation of solvent the residue was treated with water (200 mL) and kept under ice-cooling for 1 h.Crystals were filtered off and dried in air to afford the corresponding pyrazole. In some cases thus obtainedsubstance was purified by recrystallization from aqueous ethanol.
		Sodium metal (60%, 15.06 g, 376 mmol) is added to dry ethanol (300 ml_), then 1-(4-fluorophenyl)- ethanone (40.0 g, 289 mmol) in dry THF is added at 0 C and stirred for 10 min. at this temperature. Diethyl oxalate (50.78 g, 347 mmol) is added and stirred for 16 h at ambient temperature. 2 N HCI is added. The formed solid is collected by filtration and dried.
	With potassium tert-butylate; In N,N-dimethyl-formamide; at 0 - 45℃; for 1.75h;	In a three-necked flask acetophenone (5g, 41.61 mmol) anddiethyl oxalate (6.76 mL, 50 mmol) were dissolved in anhydrousDMF 65 mL at 0 C and t-BuOK (2g, 83.25 mmol) was slowly added,the mixture was stirred at 0 C for 15 min and 30 min more at roomtemperature before heating at 45 C for 1h. Reaction was pouredinto water-acetic acid and product extracted with ethyl acetate.Organic layers were combined, washed with water and brine, driedover magnesium sulphate, filtered and concentrated to yield thetitle compound. MS (ESI) m/z (%): 237.2 [M H]

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2
[ 31686-94-9 ]
[ 17852-67-4 ]
[ 1028297-80-4 ]

References: [1]Chemical and Pharmaceutical Bulletin,1997,vol. 45,p. 987 - 995.

3
[ 31686-94-9 ]
[ 640291-92-5 ]

Yield	Reaction Conditions	Operation in experiment
26%	With hydroxylamine hydrochloride; In ethanol; at 90℃;	NH2OHHC1 (2.92 g, 5.00 eq.) was added to a solution of <strong>[31686-94-9]ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate</strong> (2 g, 8.40 mmol, 1.00 eq.) in ethanol (20 mL). The resulting solution was stirred overnight at 90 C in anoil bath. The solids were filtered and the resulting mixture was concentrated under vacuum.The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:25).This resulted in 518 mg (26%) of ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate as a whitesolid. ?HNMR(400MHz, CDC13): oe 7.85-7.81 (m, 2H), 7.23-7.19 (m, 2H), 6.90 (s, 1H), 4.53-4.47 (m, 2H), 1.49-1.45 (t, J= 7.2 Hz, 3H).
26%	With hydroxylamine hydrochloride; In ethanol; at 90℃;	NH2OH HCl (2 92 g, 5.00 eq.) was added to a solution of <strong>[31686-94-9]ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate</strong> (2 g, 8.40 mmol, 1.00 eq.) in ethanol (20 mL). The resulting solution was stirred overnight at 90 C in an oil bath. The solids were filtered and the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :25). This resulted in 518 mg (26%) of ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate as a white solid. NMR (400MHz, CDC13): delta 7.85-7.81 (m, 2H), 7.23-7.19 (m, 2H), 6.90 (s, 1H), 4.53- 4.47 (m, 2H), 1.49-1.45 (t, J= 7.2 Hz, 3H).
24 g	With hydroxylamine hydrochloride; In ethanol; at 0 - 80℃; for 3h;	To a stirred solution of ethyl 4-(4- fluorophenyl)-2,4-dioxobutanoate (44.0 g, 187mmol) in ethanol (600mL) at 0 C, was added hydroxyl amine hydrochloride (39.0 g, 561mmol) portion wise at 0 C. The reaction mixture was then stirred at 80 C for 3h. The reaction mixture was concentrated under reduce pressure and the resulting residue was suspended in water (500mL). The precipitates were collected by filtration and dried under vacuum to give crude product which was purified by column chromatography (eluted in 0-15% Ethyl acetate in Hexane) to obtained ethyl 5-(4- fluorophenyl)isoxazole-3-carboxylate (24.0 g, 236 [M+H]). 1H NMR: (400 MHz, DMSO) delta: 1.601-1.610 (t, 3H), 4.468-4.530 (m, 2H), 6.898-6.908 (t,lH), 7.188-7.230 (m, 2H), 7.810-7.849 (m, 2H).

With hydroxylamine hydrochloride; In methanol;Reflux;

A mixture of 20 (3 g, 11.03 mmol) and NH2eOH.HCl (2.28 g,33.09 mmol) in MeOH (50 mL) was heated to reflux overnight. TheMeOH was then evaporated and the residue was extracted withethyl acetate, dried over Na2SO4. After filtration and concentrationin vacuo, the crude residue was purified by column to afford 21; MS(ESI)m/z (%): 236.1 [M H]; 1H NMR (400 MHz, CDCl3) d7.85e7.78(m, 2H), 7.20 (t, J 8.6 Hz, 2H), 6.89 (s, 1H), 4.01 (s, 3H).

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[7]Patent: WO2016/54560,2016,A1 .Location in patent: Page/Page column 27.
[8]Letters in drug design and discovery,2017,vol. 14,p. 712 - 717.
[9]Letters in drug design and discovery,2018,vol. 15,p. 576 - 582.
[10]Journal of Enzyme Inhibition and Medicinal Chemistry,2018,vol. 33,p. 1352 - 1361.
[11]European Journal of Medicinal Chemistry,2020,vol. 186.
[12]Chemistry and biodiversity,2020.

4
[ 31686-94-9 ]
[ 640292-06-4 ]

References: [1]Synthesis,2003,p. 2325 - 2330.
[2]Archiv der Pharmazie,2012,vol. 345,p. 386 - 392.
[3]Letters in drug design and discovery,2018,vol. 15,p. 576 - 582.

5
[ 31686-94-9 ]
[ 640291-97-0 ]

References: [1]Synthesis,2003,p. 2325 - 2330.
[2]European Journal of Pharmaceutical Sciences,2011,vol. 42,p. 180 - 191.
[3]Archiv der Pharmazie,2012,vol. 345,p. 386 - 392.
[4]Letters in drug design and discovery,2018,vol. 15,p. 576 - 582.

6
[ 31686-94-9 ]
2-[5-(4-fluorophenyl)isoxazol-3-yl]hydroxymethyl}acrylonitrile [ No CAS ]

References: [1]Synthesis,2003,p. 2325 - 2330.

7
[ 31686-94-9 ]
[ 640292-11-1 ]

References: [1]Synthesis,2003,p. 2325 - 2330.

8
[ 31686-94-9 ]
2-[5-(4-fluorophenyl)isoxazol-3-yl]hydroxymethyl}acrylic acid ethyl ester [ No CAS ]

References: [1]Synthesis,2003,p. 2325 - 2330.

9
[ 31686-94-9 ]
2-[5-(4-fluorophenyl)isoxazol-3-yl]hydroxymethyl}cyclohex-2-enone [ No CAS ]

References: [1]Synthesis,2003,p. 2325 - 2330.

10
[ 31686-94-9 ]
2-[5-(4-fluorophenyl)isoxazol-3-yl]hydroxymethyl}acrylic acid butyl ester [ No CAS ]

References: [1]Synthesis,2003,p. 2325 - 2330.

11
[ 31686-94-9 ]
5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonitrile [ No CAS ]

References: [1]Chemical and Pharmaceutical Bulletin,1997,vol. 45,p. 987 - 995.

12
[ 31686-94-9 ]
[ 1027956-06-4 ]

References: [1]Chemical and Pharmaceutical Bulletin,1997,vol. 45,p. 987 - 995.

13
[ 31686-94-9 ]
[ 1026156-15-9 ]

References: [1]Chemical and Pharmaceutical Bulletin,1997,vol. 45,p. 987 - 995.

14
[ 31686-94-9 ]
[ 1026299-78-4 ]

References: [1]Chemical and Pharmaceutical Bulletin,1997,vol. 45,p. 987 - 995.

15
[ 31686-94-9 ]
[ 866588-11-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrazine; In ethanol; for 1h;Heating / reflux;	A mixture of <strong>[31686-94-9]ethyl 3-(4-fluorobenzoyl)pyruvate</strong> (11.3 g, 47.4 mmol), hydrazine monohydrate (2.50 g, 50.0 mmol) and ethanol (50 mL) was heated under reflux for 1 hr. The reaction mixture was cooled and poured into water. The precipitated solid was collected by filtration, washed with water, and dried to give the title compound (11.0 g, quantitative) as colorless crystals. 1H NMR (CDCl3) delta: 1.41(3H, t, J=7.2Hz), 4.41(2H, q, J=7.2Hz), 7.05-7.18(3H, m), 7.76(2H, dd, J=8.2, 5.4Hz), 11.21(1 H, s).
67%	With hydrazine hydrate; In ethanol; for 1h;Reflux;	To a solution of Intermediate 1A (120 g, 504 mmol) in ethanol (1200 mL) was added hydrazine monohydrate (25.7 mL, 529 mmol) slowly and the resulting reaction mixture was refluxed for 1 h. Reaction mixture was cooled to RT, poured into ice cold water, and the resultant solid dried under vacuum to afford Intermediate 1B (80 g, 67%). MS(ES): m/z=235 [M+H]+; 1H NMR (300 MHz, CDCl3) delta ppm 7.75 (m, 2H), 7.12 (m, 2H), 7.07 (s, 1H), 4.42 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).
80 g	With hydrazine hydrate; In ethanol; for 1h;Reflux;	To a solution of Intermediate 1 A (120 g, 504 mmol) in ethanol (1200 mL) was added hydrazine monohydrate (25.7 mL, 529 mmol) slowly and the resulting reaction mixture was refluxed for 1 h. The reaction mixture was cooled to RT, poured into ice cold water and the resultant solid was filtered and dried under vacuum to afford (0371) Intermediate IB (80 g, 67%). MS(ES): m/z = 235 [M+H]+; 1H NMR (300 MHz, CDC13) delta ppm 7.75 (m, 2H), 7.12 (m, 2H), 7.07 (s, 1H), 4.42 (q, J= 7.2 Hz, 2H), 1.42 (t, J= 7.2 Hz, 3H)

	With hydrazine hydrate; acetic acid; In ethanol; at 90℃; for 3h;	General procedure: Weigh 0.1 mol (1 eq) of the intermediate compound? -diketate 2 in a 250 ml round bottom flask,6.3 g (1 eq) of 80% hydrazine hydrate was added,Add 100ml of anhydrous ethanol and 1ml of glacial acetic acid,90 C for 3 hours,TLC detection without intermediate 2, the reaction completed.System vacuum distillation solvent,A white yellowish solid.The solid is transferred to water,Stir,filter,dry,A white solid.
16.8 g	With hydrazine dihydrochloride; In ethanol; for 3h;Reflux;	General procedure: To a stirred solution of appropriate methyl ketone (0.1 mol) in dry toluene (200 mL)was added a suspension of NaH in mineral oil (60%; 0.2 mol) in portions and the mixture was warmed to50 C. At this temperature a solution of diethyl oxalate (0.15 mol) in dry toluene (60 mL) was addeddropwise under stirring. The reaction mixture was refluxed for 1.5 h. Upon cooling to room temperatureacetic acid (0.25 mol) was added dropwise. The reaction mixture was washed with water (200 mL), organicphase was dried over MgSO4 and evaporated to dryness. The obtained crude diketone was dissolved inethanol (250 mL), hydrazine dihydrochloride (0.11 mol) was added and the mixture was refluxed for 3 h.After evaporation of solvent the residue was treated with water (200 mL) and kept under ice-cooling for 1 h.Crystals were filtered off and dried in air to afford the corresponding pyrazole. In some cases thus obtainedsubstance was purified by recrystallization from aqueous ethanol.

References: [1]Patent: EP1731505,2006,A1 .Location in patent: Page/Page column 51.
[2]Organic and Biomolecular Chemistry,2015,vol. 13,p. 3416 - 3431.
[3]Patent: US9273058,2016,B2 .Location in patent: Page/Page column 61; 62.
[4]Patent: WO2015/195880,A1 .Location in patent: Page/Page column 40; 41.
Patent: ,2015, .Location in patent: Page/Page column 40; 41.
[5]Patent: CN104592116,2017,B .Location in patent: Paragraph 0114; 0115; 0116; 0117.
[6]Synlett,2018,vol. 29,p. 890 - 893.
[7]Medicinal Chemistry,2019,vol. 15,p. 743 - 754.

16
[ 31686-94-9 ]
[ 1221066-47-2 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1630 - 1633.

17
[ 31686-94-9 ]
[ 1110771-74-8 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 892 - 898.

18
[ 31686-94-9 ]
[ 1110770-28-9 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 892 - 898.

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 45℃; for 1.75h;	General procedure: In a three-necked flask acetophenone (5 g, 41.61 mmol) and diethyl oxalate (6.76 mL, 50 mmol) were dissolved in anhydrous DMF (65 mL) at 0C and NaH 60% (2 g, 83.25 mmol) was slowly added, mixture was stirred at 0C for 15 min and 30 min more at r.t before heating at 45C for 1 h. Reaction was poured onto water-acetic acid and product extracted with ethyl acetate. Organic layers were combined, washed with water and brine, dried over magnesium sulphate, filtered and concentrated to yield the title compound as an oil (62% yield). LRMS: m/z 221 (M+1)+ Retention time: 6.30 min (Method B)

20
[ 31686-94-9 ]
C₃₃H₄₀FN₅O₇ [ No CAS ]