[ CAS No. 393-06-6 ] {[proInfo.proName]}

Name: 393-06-6|4-Amino-2-(trifluoromethyl)benzoic acid|97%
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Quality Control of [ 393-06-6 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 393-06-6 ]

CAS No. :	393-06-6	MDL No. :	MFCD03407959
Formula :	C₈H₆F₃NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AMVHEVZYTGHASE-UHFFFAOYSA-N
M.W :	205.13	Pubchem ID :	3836325
Synonyms :

Calculated chemistry of [ 393-06-6 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	5.0
Num. H-bond donors :	2.0
Molar Refractivity :	42.81
TPSA :	63.32 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) :	-6.37 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.91
Log Po/w (XLOGP3) :	1.66
Log Po/w (WLOGP) :	3.15
Log Po/w (MLOGP) :	0.95
Log Po/w (SILICOS-IT) :	1.55
Consensus Log Po/w :	1.64

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.34
Solubility :	0.932 mg/ml ; 0.00454 mol/l
Class :	Soluble
Log S (Ali) :	-2.6
Solubility :	0.511 mg/ml ; 0.00249 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.3
Solubility :	1.02 mg/ml ; 0.00497 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.42

Safety of [ 393-06-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 393-06-6 ]

* 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 [ 393-06-6 ]
Downstream synthetic route of [ 393-06-6 ]

[ 393-06-6 ] Synthesis Path-Upstream 1~6

1
[ 320-37-6 ]
[ 393-06-6 ]

Reference：

2
[ 320-47-8 ]
[ 393-06-6 ]

Reference：

3
[ 393-06-6 ]
[ 630125-91-6 ]

Reference： [1] Patent: US2014/275111, 2014, A1,
[2] Patent: WO2014/141187, 2014, A1,
[3] Patent: WO2016/37578, 2016, A1,
[4] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 7, p. 623 - 628

4
[ 109-01-3 ]
[ 393-06-6 ]
[ 694499-26-8 ]

Reference： [1] Patent: CN105461659, 2016, A,

5
[ 67-56-1 ]
[ 393-06-6 ]
[ 900254-47-9 ]

Reference： [1] Patent: US2006/160803, 2006, A1, . Location in patent: Page/Page column 140

6
[ 393-06-6 ]
[ 954815-11-3 ]

Reference： [1] Patent: US2009/131468, 2009, A1, . Location in patent: Page/Page column 72
[2] Patent: WO2009/64251, 2009, A1, . Location in patent: Page/Page column 154
[3] Patent: WO2010/122089, 2010, A1, . Location in patent: Page/Page column 61

[ 393-06-6 ] Synthesis Path-Downstream 1~86

1
[ 320-37-6 ]
[ 393-06-6 ]

Reference： [1]Journal of the American Chemical Society,1954,vol. 76,p. 1051,1054

3
[ 320-47-8 ]
[ 393-06-6 ]

Reference： [1]Journal of the American Chemical Society,1954,vol. 76,p. 1051,1054

4
[ 67-56-1 ]
[ 393-06-6 ]
[ 900254-47-9 ]

Yield	Reaction Conditions	Operation in experiment
	With diazomethyl-trimethyl-silane; at 0 - 20℃;	A solution of <strong>[393-06-6]4-amino-2-(trifluoromethyl)benzoic acid</strong> (5.00 g, 21.6 mmol) in MeOH (30 mL) was cooled to 0 C. Trimethylsilyl diazomethane (2.0 M in Et2O, 31.9 mL, 63.8 mmol) was slowly added and the reaction mixture was allowed to warm to rt. The solvent was removed and the white powder redissolved in EtOAc. The organic solution was washed with sat. NaHCO3 solution, dried over Na2SO4, filtered, and concentrated to give the title compound. LCMS: (FA) ES 249.1 (M-1).

Reference： [1]Patent: US2006/160803,2006,A1 .Location in patent: Page/Page column 140

5
[ 393-06-6 ]
[ 954815-11-3 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of sodium nitrite (0.37 g, 5.36 mmol) in water (1.5 mL) was added dropwise to a cooled (0 C.) suspension of 4-amino-2-(trifluoromethyl)benzoic acid (1 g, 4.9 mmol) in hydrochloric acid (37%, 2 mL) and ice (3 g). After 20 min at 0 C. the reaction mixture was slowly added to a stirred solution of potassium iodide (8.09 g, 48.8 mmol) in water (8 mL) at 0 C. The resulting mixture was stirred at room temperature over night, dichloromethane and sodium sulfite (2.52 g, 20.0 mmol) was added, the organic phase was collected, dried over magnesium sulfate and the solvent was evaporated to give the title compound.1H NMR (DMSO-d6) delta ppm 13.78 (s, 1H) 8.11-8.24 (m, 2H) 7.49-7.66 (m, 1H); MS (ESI) m/z 315 [M-1]-.
		A solution of sodium nitrite (0.37 g, 5.36 mmol) in water (1.5 mL) was added dropwise to a cooled (0 0C) suspension of 4-amino-2-(trifluoromethyl)benzoic acid (1 g, 4.9 mmol) in hydrochloric acid (37%, 2 mL) and ice (3 g). After 20 min at 0 0C the reaction mixture was slowly added to a stirred solution of potassium iodide (8.09 g, 48.8 mmol) in water (8 mL) at 0 0C. The resulting mixture was stirred at room temperature over night, dichloromethane and sodium sulfite (2.52 g, 20.0 mmol) was added, the organic phase was collected, dried over magnesium sulfate and the solvent was evaporated to give the title compound. 1H NMR (DMSO-J6) delta ppm 13.78 (s, 1 H) 8.11 - 8.24 (m, 2 H) 7.49 - 7.66 (m, 1 H); MS (ESI) m/z 315 [M-I]".
		Intermediate 31 : 4-lodo-2-(trifluoromethyl)benzoic acid; To a suspension of 4-amino-2-(trifluoromethyl) benzoic acid (10 g, 48.7 mmol, Apollo) in water (43 ml) in an ice-water bath (internal temperature at 5 0C) was added concentrated sulphuric acid specific gravity 1.84 (7 ml_, 131 mmol). To the slight suspension was added a solution of sodium nitrite, super free flowing (3.76 g, 54.5 mmol, Aldrich) in ice cold water (20 ml) dropwise. The suspension was stirred in an ice-water bath for 20 min. To the mixture was added a solution of potassium iodide, extra pure briquettes (12.14 g, 73.1 mmol, Acros) in ice cold 1 M sulphuric acid (30 ml). The mixture was allowed to warm to ambient temperature and then heated to 800C for 45 min under nitrogen. The mixture was allowed to cool to ambient temperature. The mixture was partitioned between ethyl acetate (300 ml) and water(300 ml). The phases were separated and the organic phase washed with brine (50 ml x 2), dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound as a dark brown solid (16.7 g); LCMS: (System 4) (M-H)" = 315, tREtau =2.64 min.

Reference： [1]Patent: US2009/131468,2009,A1 .Location in patent: Page/Page column 72
[2]Patent: WO2009/64251,2009,A1 .Location in patent: Page/Page column 154
[3]Patent: WO2010/122089,2010,A1 .Location in patent: Page/Page column 61

6
[ 393-06-6 ]
[ 1272528-33-2 ]

Reference： [1]Patent: WO2011/27106,2011,A1

7
[ 393-06-6 ]
[ 1272528-36-5 ]

Reference： [1]Patent: WO2011/27106,2011,A1

8
[ 393-06-6 ]
[ 1272528-37-6 ]

Reference： [1]Patent: WO2011/27106,2011,A1

9
[ 393-06-6 ]
C₁₆H₂₃ClO₄ [ No CAS ]

Reference： [1]Patent: WO2011/27106,2011,A1

10
[ 393-06-6 ]
[ 1272528-42-3 ]

Reference： [1]Patent: WO2011/27106,2011,A1

11
[ 67-56-1 ]
[ 393-06-6 ]
methyl 3,4-dihydroxy-5-chlorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With chloro-trimethyl-silane; at 50℃;Inert atmosphere;	Step (ii): Methyl 3-chloro-4,5-dihydroxybenzoate (3)2 3A solution of 3-chloro-4,5-dihydroxybenzoic acid (2) (3.16 g, 16.76 mmol) andchlorotrimethylsilane (6.36 mL, 50.3 mmol) in MeOH (50 mL) was stirred at 50C, under nitrogen overnight. The solvent was removed in vacuo and the residue was partitioned between brine (75 mL) and EtOAc (75 mL). The organic layer was washed with brine (75 mL), dried over MgS04 and filtered. The solvent was removed in vacuo to give methyl 3- chloro-4,5-dihydroxybenzoate (3) (3.26 g, 13.68 mmol, 82 % yield): m/z 201 [M-H]- (ES"); H NMR (400 MHz, DMSO-cfe) delta: 10.17 (2H, br s), 7.38 (1 H, d), 7.35 (1 H, d), 3.78 (3H, s).

Reference： [1]Patent: WO2011/27106,2011,A1 .Location in patent: Page/Page column 107

12
[ 67-56-1 ]
[ 393-06-6 ]
[ 894796-87-3 ]

Yield	Reaction Conditions	Operation in experiment
	With chloro-trimethyl-silane;	Synthesis 354-(3,5-Dichloro-4-ethoxybenzamido)-2-(trifluoromethyl)benzoic acid (AAA-033)4-(3,5-Dichloro-4-ethoxybenzamido)-2-(trifluoromethyl)benzoic acid (AAA-033) (12 mg, 10% for final step) was prepared in essentially the same manner as for AAA-001 except that ethyl iodide was used instead of cyclopentyl bromide in step (i) and methyl 4-amino- 2-(trifluoromethyl)benzoate (prepared from <strong>[393-06-6]4-amino-2-(trifluoromethyl)benzoic acid</strong> by reaction with MeOH and TMSCI) was used instead of methyl 4-aminobenzoate in step (Hi): m/z 422 [M+H]+ (ES+); 420 [M-H]' (ES"); H NMR (400 MHz, DMSO-d6) delta: 10.77 (1 H, s), 8.26 (1 H, s), 8.14 (1 H, d), 8.10 (2H, s), 7.88 (1 H, d), 7.15 (1 H, br s), 4.14 (2H, q), 1.40 (3H, t).
20.3 g	With diazomethyl-trimethyl-silane; In dichloromethane; at 0℃; for 1h;	Trimethylsilyldiazomethane (55.57 mL, 2M, 111.15 mmol) was slowly added dropwise to a mixed solution of Compound 1a (19.00 g, 92.62 mmol) in 150 mL of methanol and 150 mL of dichloromethane. After the obtained reaction liquid was stirred at 0 C for 1 hour, the reaction mixture was quenched by adding 10 mL of water, and concentrated under reduced pressure to give Compound 1b (20.30 g).

Reference： [1]Patent: WO2011/27106,2011,A1 .Location in patent: Page/Page column 99
[2]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 798 - 814
[3]Patent: CN107936004,2018,A .Location in patent: Paragraph 0077; 0078; 0079; 0080

13
[ 10602-04-7 ]
[ 393-06-6 ]
[ 1433953-84-4 ]

Reference： [1]Advanced Synthesis and Catalysis,2012,vol. 354,p. 2905 - 2910

14
[ 393-06-6 ]
2-(1-benzyl-1H-1,2,3-triazol-4-yl)ethyl 4-((2,3-dioxo-4-(((1R,2R)-2-(piperidin-1-yl)cyclohexyl)amino)cyclobutyl)amino)-2-(trifluoromethyl)benzoate [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2012,vol. 354,p. 2905 - 2910

15
[ 393-06-6 ]
[ 1433953-85-5 ]

Reference： [1]Advanced Synthesis and Catalysis,2012,vol. 354,p. 2905 - 2910

16
[ 393-06-6 ]
[ 1433953-96-8 ]

Reference： [1]Advanced Synthesis and Catalysis,2012,vol. 354,p. 2905 - 2910

17
[ 393-06-6 ]
4-(1-benzyl-1H-1,2,3-triazol-4-yl)benzyl 4-((2,3-dioxo-4-(((1R,2R)-2-(piperidin-1-yl)cyclohexyl)amino)cyclobutyl)amino)-2-(trifluoromethyl)benzoate [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2012,vol. 354,p. 2905 - 2910

18
[ 393-06-6 ]
[ 1433953-94-6 ]

Reference： [1]Advanced Synthesis and Catalysis,2012,vol. 354,p. 2905 - 2910

19
[ 393-06-6 ]
[ 1433953-95-7 ]

Reference： [1]Advanced Synthesis and Catalysis,2012,vol. 354,p. 2905 - 2910

20
[ 393-06-6 ]
[ 927-74-2 ]
[ 1433953-93-5 ]

Reference： [1]Advanced Synthesis and Catalysis,2012,vol. 354,p. 2905 - 2910

21
[ 393-06-6 ]
[ 630125-91-6 ]

Reference： [1]Patent: US2014/275111,2014,A1
[2]Patent: WO2014/141187,2014,A1
[3]Patent: WO2016/37578,2016,A1
[4]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 623 - 628

22
[ 393-06-6 ]
2-(4-bromo-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide [ No CAS ]

Reference： [1]Patent: US2014/275111,2014,A1
[2]Patent: WO2014/141187,2014,A1

23
[ 393-06-6 ]
2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide [ No CAS ]

Reference： [1]Patent: US2014/275111,2014,A1
[2]Patent: WO2014/141187,2014,A1

24
[ 5308-25-8 ]
[ 393-06-6 ]
[ 1609677-80-6 ]

Yield	Reaction Conditions	Operation in experiment
89%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 25℃; for 2h;	A mixture of 4-amino-2-trifluoromethyl-benzoic acid (15 g, 73.1 mmol), HOBT (14.56 g, 95 mmol), EDC (16.82 g, 88 mmol), Et3N (20.38 mL, 146 mmol), 1-ethyl-piperazine (8.35 g, 73.1 mmol) in DCM (200 mL) was stirred at 25 C. for 2 h. To the mixture was added DCM (200 mL) and then washed with H2O, 2 mol/L NaOH (2*150 mL) and brine. The organic layer was dried over Na2SO4 and concentrated to give a off white solid of (4-amino-2-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (20 g, 65.2 mmol, 89.0% yield): 1H NMR (400 MHz, CDCl3) delta: 7.07 (d, J=8.0 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.79 (dd, J=2.0, 8.0 Hz, 1H), 3.99 (s, 2H), 3.84-3.76 (m, 2H), 3.25-3.23 (m, 2H), 2.50-2.39 (m, 4H), 2.33-2.31 (m, 2H), 1.08 (t, J=7.2 Hz, 3H); ES-LCMS m/z 302 (M+H).
89%	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; In dichloromethane; at 25℃; for 2h;	A mixture of 4-amino-2-trifluoromethyl -benzoic acid (15 g, 73.1 mmol), HOBT (14.56 g, 95 mmol), EDC (16.82 g, 88 mmol), Et3N (20.38 mL, 146 mmol), 1-ethyl-piperazine (8.35 g, 73.1 mmol) in DCM (200 mL) was stirred at 25 C for 2 h. To the mixture was added DCM (200 mL) and then washed with H20, 2 M NaOH (2 x 150 mL) and brine. The organic layer was dried over NaaSOzi, filtered, and concentrated to give a off white solid of (4-amino-2-trifluoromethyl-phenyl)- (4-ethyl-piperazin-l-yl)-methanone (20 g, 65.2 mmol, 89.0% yield): NMR (400 MHz, CDC13) delta: 7.07 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 2.0, 8.0 Hz, 1H), 3.99 (s, 2H), 3.84-3.76 (m, 2H), 3.25-3.23 (m, 2H), 2.50-2.39 (m, 4H), 2.33-2.31 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H); ES-LCMS m/z 302 (M+H).
89%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 25℃; for 2h;	A mixture of 4-amino-2-trifluoromethyl-benzoic acid (15 g 73.1 mmol) HOBT (14.56 g 95 mmol) EDC (16.82 g 88 mmol) Et3N (20.38 mL 146 mmol) 1-ethyl-piperazine (8.35 g 73.1 mmol) in DCM (200 mL) was stirred at 25 for 2 h. To the mixture was added DCM (200 mL) and then washed with H2O 2 mol/L NaOH (2 x 150 mL) and brine. The organic layer was dried over Na2SO4 and concentrated to give a off white solid of (4-amino-2-trifluoromethyl-phenyl) - (4-ethyl-piperazin-1-yl) -methanone (20 g 65.2 mmol 89.0yield) 1H NMR (400 MHz CDCl3) delta7.07 (d J 8.0 Hz iH) 6.92 (d J 2.4 Hz 1H) 6.79 (dd J 2.0 8.0 Hz 1H) 3.99 (s 2H) 3.84-3.76 (m 2H) 3.25-3.23 (m 2H) 2.50-2.39 (m 4H) 2.33-2.31 (m 2H) 1.08 (t J 7.2 Hz 3H) ES-LCMS m/z 302 (M+H)

Reference： [1]Patent: US2014/275111,2014,A1 .Location in patent: Paragraph 0271; 0272
[2]Patent: WO2014/141187,2014,A1 .Location in patent: Page/Page column 51; 52
[3]Patent: WO2016/37578,2016,A1 .Location in patent: Page/Page column 66
[4]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 623 - 628

25
[ 393-06-6 ]
2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide dihydrochloride [ No CAS ]

Reference： [1]Patent: US2014/275111,2014,A1
[2]Patent: WO2014/141187,2014,A1

26
[ 28920-43-6 ]
[ 393-06-6 ]
4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(trifluoromethyl)benzoic acid [ No CAS ]

Reference： [1]Green Chemistry,2015,vol. 17,p. 3122 - 3129

27
[ 393-06-6 ]
1-(4-bromo-2-(difluoromethyl)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

28
[ 393-06-6 ]
1-(2-(difluoromethyl)-4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

29
[ 393-06-6 ]
1-(2-(difluoromethyl)-4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

30
[ 393-06-6 ]
[ 1345045-32-0 ]

Reference： [1]Patent: WO2016/37578,2016,A1
[2]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 623 - 628

31
[ 393-06-6 ]
1-(4-((5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)oxy)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

32
[ 393-06-6 ]
1-(4-((5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

33
[ 393-06-6 ]
1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

34
[ 393-06-6 ]
1-(2-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-4,6-dimethylpyrimidin-5-yl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

35
[ 393-06-6 ]
1-(2-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-4,6-dimethylpyrimidin-5-yl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea trihydrochloride [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

36
[ 393-06-6 ]
[ 694499-30-4 ]

Reference： [1]Patent: WO2016/37578,2016,A1

37
[ 393-06-6 ]
1-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-3-(4-(morpholinomethyl)-3-(trifluoromethyl)phenyl)urea hydrochloride [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

38
[ 393-06-6 ]
1-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)urea dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

39
[ 393-06-6 ]
1-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1
[2]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 623 - 628

40
[ 393-06-6 ]
1-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1
[2]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 623 - 628

41
[ 393-06-6 ]
1-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1
[2]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 623 - 628

42
[ 110-91-8 ]
[ 393-06-6 ]
[ 919278-28-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 25℃; for 2h;	A solution of 4-amino-2- (trifluoromethyl) benzoic acid (1 g 4.87 mmol) morpholine (0.637 g 7.31 mmol) EDC (1.402 g 7.31 mmol) HOBt (1.120 g 7.31 mmol) and DIEA (2.55 mL 14.62 mmol) in DCM (60 mL) was stirred at 25 . After 2 h LCMS analysis showed the starting material was disappeared. The solvent was removed in vacuo and the residue was purified by column chromatography (DCM/MeOH 20/1) to give a colorless oil of (4-amino-2- (trifluoromethyl) phenyl) (morpholino) methanone (1.3 g 4.59 mmol 94yield) 1HNMR(400 MHz CD3OD) delta7.06 (d J 8.4 Hz 1H) 6.96 (d J 2.0 Hz 1H) 6.87-6.85 (m 1H) 3.74-3.66 (m 6H) 3.58-3.53 (m 2H) ES-LCMS m/z 275.1 (M+H)

Reference： [1]Patent: WO2016/37578,2016,A1 .Location in patent: Page/Page column 198

43
[ 109-01-3 ]
[ 393-06-6 ]
[ 694499-26-8 ]

Reference： [1]Patent: CN105461659,2016,A

44
[ 109-01-3 ]
[ 393-06-6 ]
[ 853297-04-8 ]

Yield	Reaction Conditions	Operation in experiment
76.5%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at -5 - 20℃;	To 2L add reaction bottle <strong>[393-06-6]2-trifluoromethyl-4-aminobenzoic acid</strong> 100g (0.488mol, 1 . 0eq) then adding 700mLDCM rear, stirring dissolution cleaning, cooling to -5 C. Start dropping raw material N-methyl piperazine 98g (0.98mol, 2 . 0eq), 3h finish dripping, maintain process temperature of not more than 0 C, stirring after adding 10-20min, EDCI140g to added in batches (0.732mol, 1 . 5eq), the feeding time 6h, after adding stirring at room temperature. TLC detection raw materials dematerialised the reaction is complete. Add water to stir and liquid separating, collecting the organic phase, the aqueous phase used for extraction of DCM, dried, crude job the filtration turns on lathe with ethanol and petroleum ether mixed solvent washing, drying, dry to near white powder solid 107g, yield: 76.5%, HPLC: 98.8%, MP156 . 0-158.0 C

Reference： [1]Patent: CN105461659,2016,A .Location in patent: Paragraph 0028; 0029; 0030; 0031; 0063; 0064; 0065; 0066

45
[ 393-06-6 ]
[ 1272527-11-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 798 - 814

46
[ 393-06-6 ]
C₁₈H₁₄Cl₂F₃NO₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 798 - 814

47
[ 393-06-6 ]
[ 18107-18-1 ]
[ 894796-87-3 ]

Yield	Reaction Conditions	Operation in experiment
20.30 g	In methanol; dichloromethane; at 0℃; for 1h;	To a mixed solution of compound 3a (19.00 g, 92.62 mmol) in 150 mL of methanol and 150 mL of dichloromethane, trimethylsilyldiazomethane (55.57 mL, 2M, 111.15 mmol) was slowly added dropwise at 0C. After the resulting reaction mixture was stirred at 0C for 1 hour, 10 mL of water was added to the reaction mixture to quench the reaction, and the mixture was concentrated under reduced pressure to give Compound 3b (20.30 g).
20.3 g	With methanol; In dichloromethane; at 0℃; for 1h;	At 0 C, trimethylsilyl diazomethane (55.57 mL, 2 M, 111.15 mmol) was slowly added dropwise to a mixed solution of Compound 63a (19.00 g, 92.62 mmol) in 150 mL of methanol and 150 mL of dichloromethane. The resulting reaction mixture was stirred for 1 hr at 0 C, and 10 mL of water was added to quench the reaction. The resulting mixture was directly concentrated under reduced pressure, to give Compound 63b (20.30 g). 1H NMR (400 MHz, CDCl3) delta 7.78-7.76 (d, J=8.8 Hz, 1H), 6.99-6.98 (d, J=2.0 Hz, 1H), 6.78-6.75 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 4.21 (s, 2H), 3.88 (s, 3H).

Reference： [1]Patent: CN107987072,2018,A .Location in patent: Paragraph 0117; 0118; 0119
[2]Patent: EP3489233,2019,A1 .Location in patent: Paragraph 0282-0283

48
[ 393-06-6 ]
C₉H₇BrF₃NO₂ [ No CAS ]

Reference： [1]Patent: CN107987072,2018,A
[2]Patent: CN107936004,2018,A
[3]Patent: EP3489233,2019,A1

49
[ 393-06-6 ]
C₉H₅BrClF₃O₄S [ No CAS ]

Reference： [1]Patent: CN107987072,2018,A
[2]Patent: EP3489233,2019,A1

50
[ 393-06-6 ]
C₁₀H₉BrF₃NO₄S [ No CAS ]

Reference： [1]Patent: CN107987072,2018,A
[2]Patent: EP3489233,2019,A1

51
[ 393-06-6 ]
C₁₄H₁₄F₅NO₆S [ No CAS ]

Reference： [1]Patent: CN107987072,2018,A

52
[ 393-06-6 ]
C₁₂H₁₂F₅NO₅S [ No CAS ]

Reference： [1]Patent: CN107987072,2018,A

53
[ 393-06-6 ]
C₁₁H₁₃F₃N₂O₄S [ No CAS ]

Reference： [1]Patent: CN107987072,2018,A
[2]Patent: EP3489233,2019,A1

54
[ 393-06-6 ]
C₁₂H₁₃F₃N₂O₄S [ No CAS ]

Reference： [1]Patent: CN107987072,2018,A
[2]Patent: EP3489233,2019,A1

55
[ 393-06-6 ]
tert-butyl (4-(4-(3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)pyridin-2-yl)(methyl)carbamate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 623 - 628

56
[ 393-06-6 ]
1-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(2-(methylamino)pyridin-4-yl)phenyl)urea [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 623 - 628

57
[ 393-06-6 ]
C₉H₅BrClF₃O₂ [ No CAS ]