79128-68-0|Methyl 3-(2,2,2-trifluoroacetamido)thiophene-2-carboxylate| Ambeed

Structure of 79128-68-0

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Quality Control of [ 79128-68-0 ] Purity: 97% SDS Specification

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Product Details of [ 79128-68-0 ]

CAS No. :	79128-68-0
Formula :	C₈H₆F₃NO₃S
M.W :	253.20
SMILES Code :	O=C(C1=C(NC(C(F)(F)F)=O)C=CS1)OC
MDL No. :	MFCD00103374
InChI Key :	CJNCTQZMIQZVQQ-UHFFFAOYSA-N
Pubchem ID :	2805185

Safety of [ 79128-68-0 ]

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

Computational Chemistry of [ 79128-68-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	5
Fraction Csp3	0.25
Num. rotatable bonds	5
Num. H-bond acceptors	6.0
Num. H-bond donors	1.0
Molar Refractivity	50.1
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	83.64 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.19
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	2.63
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.11
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.	0.91
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	2.62
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.29

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.97
Solubility	0.273 mg/ml ; 0.00108 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.	-4.04
Solubility	0.0233 mg/ml ; 0.0000919 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	-2.63
Solubility	0.587 mg/ml ; 0.00232 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	No
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.	-5.98 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	0.0 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<0.0
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)	2.49

Application In Synthesis of [ 79128-68-0 ]

* 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 [ 79128-68-0 ]

[ 79128-68-0 ] Synthesis Path-Downstream 1~35

1
[ 79128-68-0 ]
[ 79128-73-7 ]

References: [1]Synthesis,1981,p. 487 - 489.

2
[ 22288-78-4 ]
[ 407-25-0 ]
[ 79128-68-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	With pyridine; In acetonitrile; at 0 - 20℃;Product distribution / selectivity;	To a stirred solution of methyl 3-amino-thiophene-2- carboxylate (25.0 g, 159 mmol) in acetonitrile (325 mL) at 00C were added pyridine (15.5 mL) and trifluoroacetic anhydride (29.3 mL) . After 5 min, the mixture was allowed to warm to room temperature and the mixture was stirred for an additional 20 min. The mixture was poured into ice-water (3.0 L) and the mixture was stirred for 15 min. The precipitate was collected by filtration, washed with water and dried under vacuum to afford the title compound (37.3 g, 93%) as a pink solid: 1H NMR (300 MHz, DMSO-d6) delta 3.86 (3H, s) , 7.72 (IH, d, J = 5.4 Hz), 8.03 (IH, d, J = 5.4 Hz), 11.17 (IH, br s)
	With pyridine; In acetonitrile; at 0 - 20℃; for 0.416667h;	EXAMPLE 9 (S)-3- (4-OXO-6-P-TOLYL-4H-THIENO [3, 2-D] PYRIMIDIN-3-YL)-PYRROLIDINE-1- CARBOXYLIC ACID METHYL-((S)-1-METHYL-PYRROLIDEN-3-YL)-AMIDE , 1) LDA,-78C TFAA S 0 2) dibromoethane nu pyridine, CH, CN O 9a F F F NYO S Q KzCO, S Q O Br Br MeOH, HZO NH,, EtOH 9b OS 92 Fp, O' /NN-vNBoc / WOK 0 9c 0 k N CN-Boc 1) TFA/DCM Buzz F 0 Boc Br S 9f 9d HCHO JC-N NaHB (OAc)., S N I--- S N I -Sal 5 9g 9h N 9g N 9h Oh 0 Zon UL J "N"g N 9h Ph (PPh3) 4 N 1, 4-Dioxane/H20 9-1 Step 9A: Methyl 3-aminothiophene-2-carboxylate (10.0 g) in acetonitrile (130 mL) was cooled to 0C and treated with pyridine (6.2 mL) and trifluoroacetic anhydride (11.7 mL). After stirring for 5 minutes the reaction mixture was warmed to room temperature and stirred an additional 20 minutes. The reaction was poured into of ice water (1.5 L) and stirred for 15 minutes. The precipitate was collected by filtration and azeotroped with ethanol (3 x 200 mL) to yield compound 9a (15.9 g).
	In diethyl ether; at 0 - 20℃; for 2h;	To a solution of methyl 3-amino-2-thiophenecarboxylate (5 g) in ether (100 mL) at O0C under nitrogen was added slowly trifluoroacetic anhydride (4.5 mL). The reaction was stirred at room temperature for 2 h. The reaction was partitioned between diethyl ether and 2N hydrochloric acid. The organics were washed with brine, dried (Na2SO4) and evaporated to give the title compound. MS calcd for (C8H6F3NO3S - H)": 252 MS found (electrospray): (M-H)" = 252

	With pyridine; In acetonitrile; at 0 - 20℃; for 0.416667h;	Preparation of 3-(2,2,2-trifluoracetamido)thiophene-2-carboxylic acid methyl ester: Methyl-3-aminothiophene-2-carboxylate (10.0 g) in acetonitrile (130 mL) is cooled to 0 C. and treated with pyridine (6.2 mL) and trifluoroacetic anhydride (11.7 mL). Stirring is continued for 5 minutes and the reaction mixture is warmed to room temperature and stirred an additional 20 minutes. The reaction is poured into a flask containing ice water (1.5 L) and stirred for 15 minutes. The precipitate which forms is collected by filtration and azeotropically distilled with (3*200 mL) to remove any residual water and affords 15.9 g of the desired compound.
	With triethylamine; In dichloromethane; at 0 - 20℃; for 120.25h;	Intermediate 1Methyl 3-[(trifluoroacetyl)amino]-2-thiophenecarboxylateTo a stirred solution of methyl 3-amino-2-thiophenecarboxylate (10.1 g) and triethylamine (8.04 ml.) in DCM (100 ml.) at O0C was added trifluoroacetic anhydride (9.98 ml.) dropwise over 0.25 hours. The reaction mixture was allowed to warm to room temperature and was left to stand for 5 days. The mixture was evaporated in vacuo and the residue was partitioned between sodium bicarbonate solution and DCM. The organics were separated using a hydrophobic frit and were evaporated in vacuo to give the title compound. 1H NMR (CDCI3) delta 1 1.20 (1 H, br, s), 8.08 (1 H, d), 7.58 (1 H, d), 3.95 (3H, s).
	With pyridine; In acetonitrile; at 0 - 20℃;Cooling with ice;	A) Production of methyl 3-[(trifluoroacetyl)amino]thiophene-2-carboxylate To a solution of methyl 3-aminothiophene-2-carboxylate (50 g) in acetonitrile (650 mL) were added pyridine (31 mL) and trifluoroacetic anhydride (58.6 mL) while stirring under ice-cooling, and the mixture was stirred at 0C for 5 min. After stirring, the reaction system was allowed to warm to room temperature and, 10 min later, poured into ice water (6 L). After stirring for 20 min, the precipitate was collected by filtration and washed with water to give the title compound (80 g) as a pale-brown solid. 1H-NMR(DMSO-d6) delta 3.86(3H,s), 7.72(1H,d,J=5.4Hz), 8.03(1H,d,J=5.4Hz), 11.17(1H,brs).

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2535 - 2539.
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 6293 - 6302.
[3]Patent: WO2010/101302,2010,A1 .Location in patent: Page/Page column 129-130.
[4]Patent: WO2005/47293,2005,A1 .Location in patent: Page/Page column 28.
[5]Patent: WO2007/71434,2007,A1 .Location in patent: Page/Page column 27.
[6]Patent: US2007/299062,2007,A1 .Location in patent: Page/Page column 9.
[7]Patent: WO2009/818,2008,A1 .Location in patent: Page/Page column 29.
[8]Patent: EP2540728,2013,A1 .Location in patent: Page/Page column 43-44.

3
[ 79128-68-0 ]
[ 852330-31-5 ]

Yield	Reaction Conditions	Operation in experiment
41%		To a solution of N- (1-methylethyl) propan-2-amine (20 mL, 142 mmol) in THF (200 mL) was added 1.6 M n-butyl lithium in hexane (84.2 mL, 132 mmol) at 00C. After stirring at this temperature for 15 min, the mixture was cooled to - 78C. Then, a solution of methyl 3-[ (trifluoroacetyl) amino] thiophene-2-carboxylate (10.1 g, 40.0 mmol) in THF (50 itiL) was added slowly. After additional stirring at -780C for 1 h, 1, 2-dibromoethane (20.6 inL, 238 mmol) was added at once. The mixture was stirred at -78C for 30 min and at room temperature for 30 min. The mixture was poured into saturated aqueous NaHCO3 (600 mL) and extracted with EtOAc. The combined extracts were washed with brine, and then dried over Na2SO4. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 10:90 hexane/EtOAc) to give the title compound (5.30 g, 41%) as a yellow solid: 1H NMR (300 MHz, CDCl3) delta 3.94 (3H, s) , 8.11 (IH, s) , 11.15 (IH, br s) .
		Step 9B: To THF (100 mL) at-78C was added diisopropylamine (10 mL) and butyllithium (26.4 mL; 2.5 M in hexanes). The reaction mixture was warmed to 0C and stirred for 10 minutes. The reaction mixture was cooled to-78C and 9a (5.06 g) in THF (20 mL) was transferred via canula. The reaction was stirred at-78C for 1 hour, and then treated with 1,2-dibromoethane (10.3 mL) in one portion. The reaction mixture was stirred at-78C for 30 minutes, then at room temperature for 30 minutes. Saturated sodium bicarbonate solution was added and the aqueous layer was extracted with three times with ethyl acetate. The combined organic layers were washed with water and brine. The organic layer was dried over MgS04, concentrated under reduced pressure, and purified by silica gel chromatography (2.5 % ethyl acetate in hexanes) to give compound 9b (2.88 g).
		Preparation of 5-bromo-<strong>[79128-68-0]3-(2,2,2-trifluoracetamido)thiophene-2-carboxylic acid methyl ester</strong>: To THF (100 mL) at -78 C. is added diisopropylamine (10 mL) and butyllithium (26.4 mL, 2.5 Min hexanes). The reaction mixture is allowed to warm ot 0 C. and stir for 10 minutes. The reaction mixture is re-cooled to -78 C. and <strong>[79128-68-0]3-(2,2,2-trifluoracetamido)thiophene-2-carboxylic acid methyl ester</strong> (5.06 g) dissolved in THF (20 mL) is added via cannula. The reaction is stirred at -78 C. for 1 hour and then treated with 1,2-dibromoethane (10.3) added in one portion. The reaction is stirred an additional 30 minutes at -78 C. then allowed to warm to room temperature for 30 minutes. NaHCO3 (sat. solution) is added and the aqueous layer extracted with EtOAc (*3). The combined organic layers are washed with water and brine. The organic layer is dried and concentrated under reduced pressure and purified over silica (2.5% EtOAc in hexanes) to afford 2.88 g of the desired product.

B) Production of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate To a solution of diisopropylamine (20 mL) in tetrahydrofuran (200 mL) was added 1.6M n-butyllithium/hexane solution (82.4 mL) while stirring under ice-cooling, and the mixture was stirred at 0C for 15 min. After stirring, the reaction system was cooled to -78C, and a solution of <strong>[79128-68-0]methyl 3-[(trifluoroacetyl)amino]thiophene-2-carboxylate</strong> (10 g) in tetrahydrofuran (50 mL) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr, and 1,2-dibromoethane (20.6 mL) was added. After stirring at the same temperature for 30 min, the reaction system was allowed to warm to room temperature, and further stirred for 30 min. The reaction system was poured into saturated aqueous sodium hydrogen carbonate (600 mL), and the mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.3 g) as a yellow solid. 1H-NMR(CDCl3) delta 3.94(3H,s), 8.11(1H,s), 11.15(1H,brs).

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2535 - 2539.
[2]Patent: WO2010/101302,2010,A1 .Location in patent: Page/Page column 177-178.
[3]Patent: WO2005/47293,2005,A1 .Location in patent: Page/Page column 29.
[4]Patent: US2007/299062,2007,A1 .Location in patent: Page/Page column 9.
[5]Patent: EP2540728,2013,A1 .Location in patent: Page/Page column 44.

4
[ 79128-68-0 ]
[ 107818-55-3 ]

Yield	Reaction Conditions	Operation in experiment
18%		To stirred tetrahydrofuran (100 inL) at -78C were added dropwise diisopropylamine (9.00 mL, 63.9 mmol) and n-butyl lithium (37.1 mL, 59.4 mmol, 1.6 M solution in n-hexane) successively. The reaction mixture was allowed to warm to 00C and stirred for additional 10 min. The mixture was cooled to -78C again and methyl 3- (2,2, 2- trifluoroacetamido) thiophene-2-carboxylate (4.56 g, 18.0 mmol) was added to the mixture. After 1 h, bromine (2.78 mL, 54.0 mmol) was added to the mixture, and stirring was continued at -78C for 2 h and at room temperature for 30 min. The mixture was then poured into sat. aqueous sodium hydrogen carbonate (180 mL) . Extraction with ethyl acetate (150 mL) , washing with brine, drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was purified by column chromatography (Combiflash, 12 g silica gel, hexanes to 90:10 hexanes/ethyl acetate) to afford a mixture of the title compound and methyl 3-aminothiophene-2-carboxylate (1.86 g) as a white solid. The ratio was about 2:1 estimated by 1H NMR analysis:1H NMR (300 MHz, DMSO-d6) delta 3.84 (3H, s) , 7.79 (IH, s) , 11.22 (IH, br s) .A mixture of methyl 5-bromo-3- (2, 2, 2- trifluoroacetamido) thiophene-2-carboxylate (1.86 g) , potassium carbonate (3.72 g, 26.9 mmol), methanol (40 mL) and water (10 mL) was stirred at room temperature for 1.5 h. The mixture was concentrated in vacuo and then ethyl acetate and water were added to the residue for extraction. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (Combiflash, silica gel, hexanes to 90:10 hexanes/ethyl acetate) to afford the title compound (0.781 g, 18% from methyl 3- (2, 2, 2-trifluoroacetamido) thiophene-2- carboxylate) as a white solid:1H NMR (300 MHz, DMSO-d6) delta 3.70 (3H, s), 6.69 (2H,br s) , 6.75 (IH, s).

References: [1]Patent: WO2010/101302,2010,A1 .Location in patent: Page/Page column 130-131.
[2]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2535 - 2539.
[3]Patent: EP2540728,2013,A1 .

5
[ 79128-68-0 ]
[ 852330-32-6 ]