[ CAS No. 849020-87-7 ] {[proInfo.proName]}

Name: 849020-87-7|6-Hydroxy-4-(trifluoromethyl)nicotinic acid|95%
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SKU: A340859
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Quality Control of [ 849020-87-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 849020-87-7 ]

SDS Specification

Alternatived Products of [ 849020-87-7 ]

Product Details of [ 849020-87-7 ]

CAS No. :	849020-87-7	MDL No. :	MFCD06245493
Formula :	C₇H₄F₃NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WCUKVMMGYGOCGJ-UHFFFAOYSA-N
M.W :	207.11	Pubchem ID :	2782930
Synonyms :

Calculated chemistry of [ 849020-87-7 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	7.0
Num. H-bond donors :	2.0
Molar Refractivity :	38.22
TPSA :	70.42 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) :	-6.68 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.01
Log Po/w (XLOGP3) :	1.24
Log Po/w (WLOGP) :	2.66
Log Po/w (MLOGP) :	-0.2
Log Po/w (SILICOS-IT) :	1.33
Consensus Log Po/w :	1.21

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.09
Solubility :	1.68 mg/ml ; 0.00812 mol/l
Class :	Soluble
Log S (Ali) :	-2.32
Solubility :	0.999 mg/ml ; 0.00482 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.72
Solubility :	3.97 mg/ml ; 0.0192 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.81

Safety of [ 849020-87-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H320-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 849020-87-7 ]

* 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 [ 849020-87-7 ]

[ 849020-87-7 ] Synthesis Path-Downstream 1~25

1
[ 849020-87-7 ]
C₂₁H₁₉F₃N₂O₅ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 193 - 198

2
[ 849020-87-7 ]
C₂₃H₂₃F₃N₂O₅ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 193 - 198

3
[ 849020-87-7 ]
C₂₀H₁₇F₃N₂O₅ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 193 - 198

4
[ 849020-87-7 ]
[ 106-95-6 ]
C₁₀H₈F₃NO₃ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 193 - 198

5
[ 849020-87-7 ]
5-bromo-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)aniline [ No CAS ]
N-(5-bromo-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		In a 10 mL MW vial a suspension of 6-hydroxy-4- (trifluoromethyl)nicotinic acid (1111 mg, 5.37 mmol) in pyridine, anhydrous (6509 mu, 80 mmol) was added slowly diethyl chlorophosphate (795 mu, 5.50 mmol) at RT in an atmosphere of nitrogen. The reaction mixture was stirred at RT for 2 h. The suspension turned solution and then suspension again. To this 5-bromo-2-((3S,5R)- 3,4,5-trimethylpiperazin-l-yl)aniline (400 mg, 1.341 mmol) was added and the reaction was heated at 70 C for 3 h. After completion, pyridine was removed in vacuo and the residue partitioned between ethyl acetate (3 mL) and saturated sodium bicarbonate solution (3 mL). The suspension was stirred for 10 min. The organic layer was separated, dried over anhydrous Na2S04. The solvent was evaporated in vacuo yielding the crude product by flash column chromatography on silica gel (0- 100%, 89% CH2C12, 10% MeOH, 1% NH4Ac/CH2Cl2) to afford the desired compound (537 mg, 80%). XH NMR (500 MHz, MeOD) delta 8.19 (d, J = 2.3 Hz, 1H), 7.93 (s, 1H), 7.32 (dd, J = 8.6, 2.3 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.90 (s, 1H), 2.93 (d, J = 11.3 Hz, 2H), 2.61 (t, J = 11.1 Hz, 2H), 2.53 (ddd, J = 10.3, 6.2, 3.2 Hz, 2H), 2.37 (s, 3H), 1.15 (d, J = 6.2 Hz, 6H); LCMS [M+l]+ = 486.0 g/mol.

Reference： [1]Patent: WO2017/147701,2017,A1 .Location in patent: Paragraph 00343; 00348-00349

6
[ 849020-87-7 ]
(4-(3-amino-2'-fluoro-5'-(morpholinomethyl)-[1,1'-biphenyl]-4-yl)-1-methylpiperazin-2-yl)methyl pivalate [ No CAS ]
4-((2'-fluoro-5'-(morpholinomethyl)-3-(6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamido)-[1,1'-biphenyl]-4-yl)-1-methylpiperazin-2-yl)methyl pivalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.8%	With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 1,4-dioxane; at 80℃; for 16h;	To a solution of (4-(3-amino-2'-fluoro-5'-(mo holinomethyl)-[l,Gamma-biphenyl]-4-yl)-l- methylpiperazin-2-yl)methyl pivalate (82 mg, 0.164 mmol) and 6-hydroxy-4- (trifluoromethyl)nicotinic acid (44.3 mg, 0.214 mmol) in 1,4-dioxane (4 mL), propylphosphonic anhydride solution (0.294 ml, 0.493 mmol) followed by pyridine (1 ml) were added. The suspension was heated to 80 C for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was concentrated to dryness and loaded onto celite and purified by flash column chromatography on silica gel (0-100%, 89% CH2C12, 10% MeOH, 1 % NH4Ac/CH2Cl2) to get the title compound (64 mg, 0.088 mmol, 53.8 % yield) as a brown solid. H NMR (500MHz, DMSO-d6) delta = 12.55 (br. s., 1H), 9.49 (s, 1H), 7.97 (d, J= 6.5 Hz, 2H), 7.42 - 7.38 (m, 1H), 7.37 - 7.30 (m, 2H), 7.29 - 7.23 (m, 2H), 6.81 (s, 1H), 4.15 (d, J = 4.3 Hz, 1H), 4.07 (s, 1H), 3.57 (t, J= 4.3 Hz, 4H), 3.50 (s, 2H), 3.11 - 2.97 (m, 2H), 2.86 - 2.82 (m, 1H), 2.71 - 2.61 (m, 1H), 2.47 - 2.41 (m, 1H), 2.37 (br. s., 5H), 2.31 (s, 3H), 1.11 (s, 9H); LCMS [M+l]+ = 688.8 g/mol.

Reference： [1]Patent: WO2017/147701,2017,A1 .Location in patent: Paragraph 00396; 00404-00405

7
[ 849020-87-7 ]
4-(3,4-dimethylpiperazin-1-yl)-2'-fluoro-5'-(morpholinomethyl)-[1,1'-biphenyl]-3-amine [ No CAS ]
N-(4-(3,4-dimethylpiperazin-1-yl)-2'-fluoro-5'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-hydroxy-4-(trifluoromethyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40.5%		In a 10 mL MW vial a suspension of 6-hydroxy-4- (trifluoromethyl)nicotinic acid (52.0 mg, 0.251 mmol) in pyridine (1.0 mL) and N,N- diisopropylethylamine (32.4 mg, 0.251 mmol) was added slowly diethyl chlorophosphate (43.3 mg, 0.251 mmol) at RT in an atmosphere of nitrogen. The reaction mixture was stirred at RT for 2 hours. The suspension turned solution and then suspension again. To this, 4-(3,4-dimethylpiperazin-l-yl)-2'-fluoro-5'- (morpholinomethyl)-[l,l'-biphenyl]-3-amine (25 mg, 0.063 mmol) in dichloromethane (2 mL) was added and the reaction was heated at 80 C for 16 hours. After completion, pyridine was removed in vacuo and the residue partitioned between dichloromethane (3 mL) and saturated sodium bicarbonate solution (3 mL). The suspension was stirred for 10 min. The organic layer was separated, dried over anhydrous Na2SC>4. The solvent was evaporated in vacuo yielding the crude product by flash column chromatography on silica gel (0-100%, 89% CH2C12, 10% MeOH, 1% NH4Ac/CH2Cl2) to afford the title compound (0.025 mmol, 40.5 % yield) as a yellow powder. XH NMR (500MHz, DMSO-d6) delta = 9.35 (s, 1H), 7.88 (d, J = 4.9 Hz, 2H), 7.32 - 7.28 (m, IH), 7.26 - 7.20 (m, 2H), 7.19 - 7.14 (m, 2H), 6.72 (s, IH), 3.48 (t, J = 4.3 Hz, 4H), 3.41 (s, 2H), 2.96 - 2.85 (m, 2H), 2.81 - 2.67 (m, 2H), 2.38 - 2.32 (m, IH), 2.28 (br. s., 6H), 2.19 - 2.16 (m, IH), 2.14 (s, 3H), 0.91 (d, J = 6.2 Hz, 3H); LCMS [M+H]+ = 588.7 g/mol.

Reference： [1]Patent: WO2017/147701,2017,A1 .Location in patent: Paragraph 00279; 00286-00287

8
[ 849020-87-7 ]
5-bromo-4-fluoro-2-(4-methylpiperazin-1-yl)aniline [ No CAS ]
N-(5-bromo-4-fluoro-2-(4-methylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		In a 10 niL MW vial a suspension of 6-hydroxy-4- (trifluoromethyl)nicotinic acid (719 mg, 3.47 mmol) in pyridine, anhydrous (4210 mu, 52.1 mmol) was added slowly diethyl chlorophosphate (514 mu, 3.56 mmol) at RT in an atmosphere of nitrogen. The reaction mixture was stirred at RT for 2 h. The suspension turned solution and then suspension again. To this 5-bromo-4-fluoro-2-(4- methylpiperazin-l-yl)aniline (250 mg, 0.868 mmol) was added and the reaction was heated at 70 C for 3 h. After completion, pyridine was removed in vacuo and the residue partitioned between ethyl acetate (3 mL) and saturated sodium bicarbonate solution (3 mL). The suspension was stirred for 10 min. The organic layer was separated, dried over anhydrous Na2S04. The solvent was evaporated in vacuo yielding the crude product by flash column chromatography on silica gel (0-100%, 89% CH2C12, 10% MeOH, 1% NH4Ac/CH2Cl2) to afford the desired compound. XH NMR (500 MHz, MeOD) delta 8.12 (d, J = 7.4 Hz, 1H), 7.93 (s, 1H), 7.12 (d, J = 10.1 Hz, 1H), 6.91 (s, 1H), 2.96 (t, J = 4.6 Hz, 4H), 2.64 (s, 4H), 2.36 (s, 3H); LCMS [M+l]+ = 459.4 g/mol.
		In a 10 ml microwave vial to a suspension of <strong>[849020-87-7]6-hydroxy-4-(trifluoromethyl)nicotinic acid</strong> (719 mg, 3.47 mmol) in anhydrous pyridine (4210 mu, 52.1 mmol) was slowly added diethyl chlorophosphate (514 mu, 3.56 mmol) at RT in an atmosphere of N2. The reaction mixture was stirred at RT for 2 h. The suspension turned into a solution and then into a suspension again. To this mixture, 5-bromo-4- fluoro-2-(4-methylpiperazin-1-yl)aniline (250 mg, 0.868 mmol) was added and the reaction was heated at 70 C for 3 h. After completion of the reaction, pyridine was removed in vacuo and the residue partitioned between ethyl acetate (3 mL) and saturated sodium bicarbonate solution (3 mL). The suspension was stirred for 10 min. The organic layer was separated, and dried over anhydrous Na2SC>4. The solvent was evaporated in vacuo yielding the crude product that was purified by flash column chromatography on silica gel (0-100%, 89% CH2C12, 10% MeOH, 1% NH4Ac/CH2Cl2) to afford the desired compound. LCMS C8 [M+l]+ = 459.4

Reference： [1]Patent: WO2017/147701,2017,A1 .Location in patent: Paragraph 00294-00296
[2]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00203

9
[ 849020-87-7 ]
5-bromo-4-fluoro-2-(4-methylpiperazin-1-yl)aniline [ No CAS ]
N-(2’,6-difluoro-4-(4-methylpiperazin-1-yl)-5’-(morpholinomethyl)-[1,1’-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2017/147701,2017,A1

10
[ 849020-87-7 ]
5-bromo-2-(4-methyl-piperazin-1-yl)-phenylamine [ No CAS ]
N-(5-bromo-2-(4-methylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%		The <strong>[849020-87-7]6-hydroxy-4-(trifluoromethyl)nicotinic acid</strong> (1.890 g, 8.94 mmol) was suspended in SOCl2 (24.33 mL, 335 mmol) and stirred at 80 C for 2 h. The solution become clear, and was then cooled to 23 C. The excess SOCl2 was removed under reduced pressure, and the resulting solid was dried under vacuum for 2 h. The dry residue was dissolved in CH2C12 (10 mL) and added over a 30 min period to a solution of 5-bromo-2-(4-methylpiperazin-l-yl)aniline (2.013 g, 7.45 mmol) and pyridine (1.801 mL, 22.36 mmol) in CH2C12 (20 mL). The resulting mixture was then stirred for 12 h. The reaction was diluted with saturated aqueous sodium bicarbonate solution (100 niL), sonicated to dissolve any solid particles, and extracted with CH2CI2 (4 x 50 mL). The combined organic extracts were dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel [0-100%, 89% CH2C12, 10% MeOH, 1% NH4Ac/CH2Cl2] to afford the title compound (366 mg, 10% yield) as a yellow solid. XH NMR (500 MHz, MeOD) delta 8.20 (d, J = 2.3 Hz, 1H), 7.95 (s, 1H), 7.32 (dd, J = 8.6, 2.3 Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 6.91 (s, 1H), 2.95 (t, J = 4.8 Hz, 4H), 2.69 (s, 4H), 2.40 (s, 3H); HRMS (ESI) m/z calcd for [M+H]+ = 459.0643, found: 459.0647 g/mol.

Reference： [1]Patent: WO2017/147701,2017,A1 .Location in patent: Paragraph 00213; 00218-00219

11
[ 849020-87-7 ]
6-fluoro-4-(4-methylpiperazin-1-yl)-3‘-(morpholinomethyl)-[1,1‘-biphenyl]-3-amine [ No CAS ]
N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-[3-(morpholin-4-ylmethyl)phenyl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.6%		Diethyl chlorophosphate (0.045 ml, 0.312 mmol) was added to a solution of <strong>[849020-87-7]6-hydroxy-4-(trifluoromethyl)nicotinic acid</strong> (0.065 g, 0.312 mmol) in pyridine, anhydrous (0.945 ml, 11.70 mmol) at room temperature under nitrogen. After stirring for lh, this solution was added to a vial containing 6-fluoro-4-(4- methylpiperazin-1-yl)-3'-(mo holinomethyl)-[l, -biphenyl]-3-amine (step 3 from (a): 0.030 g, 0.078 mmol) under nitrogen and the reaction was heated to 70C for 3 hours. The pyridine was removed under reduced pressure and LCMS of the residue (dissolved in DCM, MeCN and MeOH) indicated complete conversion to the desired product. The mixture was loaded onto celite purified by flash chromatography [0.5-10% DCM/MeOH + 1% NH4OH] to methylpiperazin-1-yl)-3'-(mo holinomethyl)-[l,Gamma- biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxarnide (0.024 g, 0.042 mmol, 53.6% yield) as a clear film. NMR (500 MHz, DMSO-d6) delta = 9.53 (s, 1H), 7.94 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.40 - 7.38 (m, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.08 (d, J=12.5 Hz, 1H), 6.81 (s, 1H), 3.60 - 3.57 (m, 4H), 3.53 (s, 2H), 2.93 (br. s., 4H), 2.38 (br. s., 4H), 2.24 (s, 3H); LCMS [M+H]+ 574 g/mol.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00201

12
[ 849020-87-7 ]
N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-[6-(oxan-4-yloxy)pyridin-3-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide [ No CAS ]