155377-05-2|Methyl 6-(trifluoromethyl)picolinate| Ambeed

Structure of 155377-05-2

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]} Purity: {[proInfo.pro_purity]}

Change View

Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days

{[ item.pr_size ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of [ 155377-05-2 ] Purity: 97% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support

Product Details of [ 155377-05-2 ]

CAS No. :	155377-05-2
Formula :	C₈H₆F₃NO₂
M.W :	205.13
SMILES Code :	O=C(OC)C1=NC(C(F)(F)F)=CC=C1
MDL No. :	MFCD02090527
InChI Key :	AYABEJGGSWJVPN-UHFFFAOYSA-N
Pubchem ID :	45158822

Safety of [ 155377-05-2 ]

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

Computational Chemistry of [ 155377-05-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	3
Num. H-bond acceptors	6.0
Num. H-bond donors	0.0
Molar Refractivity	40.52
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	39.19 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.79
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	1.96
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.04
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.	1.4
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	2.24
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.09

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.47
Solubility	0.702 mg/ml ; 0.00342 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.	-2.41
Solubility	0.802 mg/ml ; 0.00391 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	-2.99
Solubility	0.208 mg/ml ; 0.00101 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	No
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.	-6.16 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<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)	1.68

Application In Synthesis of [ 155377-05-2 ]

* 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 [ 155377-05-2 ]

[ 155377-05-2 ] Synthesis Path-Downstream 1~35

1
[ 186581-53-3 ]
[ 124-38-9 ]
[ 368-48-9 ]
[ 155377-05-2 ]
methyl 6-(trifluoromethyl)pyridine-3-carboxylate [ No CAS ]

References: [1]European Journal of Organic Chemistry,2003,p. 1569 - 1575.

2
[ 459-22-3 ]
[ 155377-05-2 ]
[ 476472-37-4 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3581 - 3584.

3
[ 155377-05-2 ]
[ 476472-46-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3581 - 3584.

4
[ 155377-05-2 ]
3-(4-fluoro-phenyl)-2-(6-trifluoromethyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3581 - 3584.

5
[ 155377-05-2 ]
[ 476473-39-9 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3581 - 3584.

6
[ 67-56-1 ]
[ 201230-82-2 ]
[ 39890-95-4 ]
[ 155377-05-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; at 60℃; for 17h;	Add palladium(II) acetate (200 mg, 2 w/w%) and l,l '-bis(diphenylphosphino)ferrocene (dppf) (400 mg, 4 w/w%) to a solution of 2-chloro-6-trifluoromethyl-pyridine (10.0 g, 55.1 mmol) in methanol (30 mL). To the orange solution add triethylamine (8.45 mL, 60.6 mmol). Purge the mixture with nitrogen and then maintain under an atmosphere of carbon monoxide (40 psig) at 60 0C for 17 h. Cool to ambient temperature and concentrate under a reduced pressure. Dissolve the solid in tert-butylmethyl ether (70 mL). Filter the resulting slurry over silica gel (10 g) and diatomaceous earth (10 g).Concentrate the filtrate to afford the title compound as a light orange solid (10.8 g, 96%). 1H NMR (399.84 MHz, DMSO d6): 8.31-8.27 (m, IH), 8.14 (dd, J= 2.4, 6.4 Hz, 2H), 3.91 (s, 3H). HRMS (ESI) m/z (M+H)+ calcd for C8H7F3NO2: 206.0423, found 206.0422.
	With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; triethylamine; at 60℃; for 22h;	Step 1: Preparation of 6-trifluomethyl-pyridine-2-carboxylic acid methyl ester (2) To a solution of 2-chloro-6-trifluoromethyl-pyridine (2 g, 11.1 mmol, 1.0 eq) in MeOH (20 mL) was add Pd(OAc)2 (124 mg, 0.05 eq) and dppf (600 mg, 0.1 eq) under an atmosphere of nitrogen. Et3N (2.3 mL, 1.5 eq) was then added to the resulting orange solution. The reaction solution was then stirred under an atmosphere of carbon monoxide (40 psi) at 60 C. for 22 hr. Once the reaction completed, the mixture was filtered and the filtrate was concentrated in high vacuum. The residue was purified by column chromatography to afford the desired product. 1HNMR (400 MHz, CDCl3): delta 8.32 (d, J=8 Hz, 1H), 8.06 (t, J=8 Hz, 1H), 8.88 (d, J=8 Hz, 1H), 4.04 (s, 3H). LC-MS: m/z 206 (M+H)+.
	With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; triethylamine; In methanol; at 60℃; under 2068.65 Torr; for 22h;Inert atmosphere;	Step 1: Preparation of 6-trfluomethyl-pyridine-2-carboxylic acid methyl ester (2). To a solution of 2-chloro-6-trifluoromethyl-pyridine (2 g, 11.1 mmol, 1.0 eq) in MeOH (20 mL) was add Pd(OAc)2 (124 mg, 0.O5eq) and dppf (600 mg, 0.leq) under an atmosphere of nitrogen. Et3N (2.3 mL, 1 .5eq) was then added to the resulting orange solution. The reaction solution was then stirred under an atmosphere of carbon monoxide (40 psi) at 60C for 22 hr. Once the reaction completed, the mixture was filtered and the filtrate was concentrated in high vacuum. The residue was purified by column chromatography to afford the desired product.?HNMR (400 MHz, CDC13): 8.32 (d, J 8 Hz, 111), 8.06 (t, J= 8 Hz, 111), 8.88 (d, J= 8 Hz, 111), 4.04 (s, 3H).LC-MS: m/z 206 (M+H).

References: [1]Patent: WO2009/131814,2009,A2 .Location in patent: Page/Page column 45.
[2]Patent: US2015/18328,2015,A1 .Location in patent: Paragraph 0720-0721.
[3]Patent: WO2015/3640,2015,A1 .Location in patent: Page/Page column 156.

7
[ 676-58-4 ]
[ 155377-05-2 ]
[ 1192356-23-2 ]

Yield	Reaction Conditions	Operation in experiment
90%		Add -trifluoromethyl-pyridine^-carboxylic acid methyl ester (80.0 g, 390 mmol) to a mixture of THF (240 mL) and tert-butylmethyl ether (400 mL). Add the solution slowly to a 3 M methylmagnesium chloride in THF (390 mL, 1.17 moles) and maintain 8 0C to 16 0C. Cool the mixture to 0 0C and add a mixture of 5 M hydrochloric acid (257 mL, 1.29 moles) and water (200 mL). Separate the phases and concentrate the organic phase under reduced pressure. Add heptane (160 mL) and cool the mixture to 5 0C. Collect the precipitate by vacuum filtration and rinse the solid with heptane (20 mL) followed by pentane (30 mL). Vacuum dry the solid to afford the title compound as a tan solid (72.3 g, 352 mmol, 90 %). 1H NMR (400 MHz, DMSO d6) delta 8.04 (t, J= 7.7 Hz, IH), 7.94 (d, J= 7.9 Hz, IH), 7.69 (d, J= 7.0 Hz, IH), 5.40 (s, IH), 1.43 (s, 6H). HRMS (ESI) m/z (M+H)+ calcd for C9Hi0F3NO : 206.0787, found 206.0787.

References: [1]Patent: WO2009/131814,2009,A2 .Location in patent: Page/Page column 46.

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In water; at 80℃; for 48h;	General procedure: Example 3, step 1: Preparation of 6-chloro-pyridine-2-carboxylic acid methyl ester (10). To a solution of 6-chloro-pyridine-2-carboxylic acid (48 g, 0.31 mol) in methanol (770 ml) was added concentrated HC1 (6 ml). The mixture was stirred at 80C for 48 hours then concentrated to remove the volatile. The crude product was diluted with ethyl acetated and washed with Sat. NaHCC"3 solution. The organic layer was dried with anhydrous Na2S04 and concentrated to give -chloro-pyridine-2-carboxylic acid methyl ester as a white solid. LC-MS: m/z 172.0 (M+H)+.
	With hydrogenchloride; In water; at 80℃; for 48h;	General procedure: To a solution of 6-chloro-pyridine-2-carboxylic acid (48 g, 0.31 mol) in methanol (770 ml) was added concentrated HCl (6 ml). The mixture was stirred at 80C for 48 hours then concentrated to remove the volatile. The crude product was diluted with ethyl acetated and washed with Sat. NaHC03 solution. The organic layer was dried with anhydrous Na2S04 and concentrated to give 6-chloro-pyridine-2-carboxylic acid methyl ester as a white solid. LC-MS: m/z 172.0 (M+H)+.

9
[ 26218-75-7 ]
(1,10-phenanthroline)(trifluoromethyl)copper(I) [ No CAS ]
[ 155377-05-2 ]

References: [1]Organic Letters,2014,vol. 16,p. 1744 - 1747.

10
[ 155377-05-2 ]
[6-chloro-2-(6-trifluoromethylpyridin-2-yl)pyrimidin-4-yl]isopropylamine [ No CAS ]

References: [1]Patent: WO2015/6591,2015,A1 .

11
[ 155377-05-2 ]
N-isopropyl-N'-pyridin-2-yl-2-(6-trifluoromethylpyridin-2-yl)pyrimidine-4,6-diamine [ No CAS ]

References: [1]Patent: WO2015/6591,2015,A1 .

12
[ 155377-05-2 ]
4,6-dichloro-2-(6-(trifluoromethyl)pyridin-2-yl)pyrimidine [ No CAS ]

References: [1]Patent: WO2015/6591,2015,A1 .

13
[ 108-13-4 ]
[ 155377-05-2 ]
2-(6-trifluoromethyl-pyridin-2-yl)-1H-pyrimidine-4,6-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium; In ethanol; for 1h;Reflux;	Step 1: Preparation of 2-(6-Trifluoromethyl-pyridin-2-yl)-1H-pyrimidine-4, 6-dione To a solution of sodium (32 g, 0.16 mol) in ethanol (500 mL) was added 6-trifluoro- methylpyridine-2-carboxylic acid methyl ester (6.15 g, 3 mmol) and malonamide (1.02 g, 1 mmol). The mixture was heated to reflux for 1 hour, then concentrated to give a residue which was poured to water (100 mL). Saturated NaHCO3 solution was added to adjust to pH 7, the mixture was filtered, and then added iN HC1 solution to adjust pH to 3. DCM (20 mL) was added, and the precipitated solid was collected by filtration and dried to give 2-(6-trifluoromethyl-pyridin-2-yl)- 1 H-pyrimidine-4,6-dione. LCMS: [M+ 1] = 257.9

References: [1]Patent: WO2015/6591,2015,A1 .Location in patent: Page/Page column 122.

14
[ 155377-05-2 ]
[ 1446507-40-9 ]

References: [1]Patent: US2015/18328,2015,A1 .
[2]Patent: WO2015/18060,2015,A1 .
[3]Patent: WO2015/17821,2015,A2 .
[4]Patent: WO2015/3640,2015,A1 .
[5]Patent: WO2016/53850,2016,A1 .
[6]Patent: WO2016/126798,2016,A1 .
[7]Patent: WO2017/24134,2017,A1 .
[8]Patent: WO2017/66611,2017,A1 .
[9]Patent: WO2017/69878,2017,A1 .
[10]Patent: EP3330258,2018,A1 .
[11]Patent: US2018/64715,2018,A1 .
[12]Patent: US2018/311249,2018,A1 .
[13]Patent: CN109265444,2019,A .
[14]Patent: EP3489230,2019,A1 .
[15]Patent: CN110054615,2019,A .
[16]Patent: CN110054614,2019,A .
[17]Patent: CN110054617,2019,A .

15
[ 155377-05-2 ]
N2,N4-bis ((R)-1-cyclopropylethyl)-6-(6-(trifluoromethyl)-pyridin-2-yl)-1,3,5-triazine-2,4-diamine [ No CAS ]

References: [1]Patent: US2015/18328,2015,A1 .
[2]Patent: WO2015/3640,2015,A1 .

16
[ 155377-05-2 ]
N²,N⁴-bis((1S,3S)-3-(4-fluorophenyl)cyclobutyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine [ No CAS ]

References: [1]Patent: US2015/18328,2015,A1 .

17
[ 155377-05-2 ]
(R)-4-chloro-N-(1-cyclopropylethyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine [ No CAS ]

References: [1]Patent: US2015/18328,2015,A1 .
[2]Patent: WO2015/3640,2015,A1 .

18
[ 155377-05-2 ]
N²-((R)-1-cyclopropylethyl)-N⁴-(pentan-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine [ No CAS ]

References: [1]Patent: US2015/18328,2015,A1 .
[2]Patent: WO2015/3640,2015,A1 .

19
[ 108-19-0 ]
[ 155377-05-2 ]
[ 1446507-38-5 ]

Yield	Reaction Conditions	Operation in experiment
71%		100801 Mixture of methyl 6-(trifluoromethyl)picolinate (50g, 244 mmol, 1.0 eq.) and biuret (30.2 g, 293 mmol, 1.20 eq.) in 750 mL EtOH was stirred at 30-35C for 10-20 mm. Titanium tetraethoxide (Ti(OEt)4, 27.8g, 122 mmol, 0.5 eq.) was added and stirred at 30-35C for 30-60 mi EtONa solution in EtOH (350 g, 19% wt, 978 mmol, 4.0 eq.) was added, and the reaction mixture was heated at 55-65C for 3 hours. The reaction mixture was concentrated, cooled to room temperature, and diluted with 700 mL water. Concentrated HC1 solution was added to adjust pH value to pH1. Methylene chloride (DCM, 700 mL) was charged, and the slurry was stirred 20-30C for 5-7 hours. Solid was collected by filtration, and the cake was sequentially washed twice with 6N HC1, twice with water, and once with DCM. The wet cake was dried at 50-60C under vacuum, yielding 6-(6-(trifluoromethyl)pyridin-2-yl)- 1,3 ,5-triazine-2,4( 1H,3H)- dione as off-white solid (45.0 g, 174 mmol, 71% yield).
47.5%	With sodium ethanolate; In ethanol; for 2h;Reflux; Inert atmosphere;	Step 2: 6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione Under the protection of nitrogen gas, to a solution of sodium ethoxide (11.2 g, 165.0 mmol) in ethanol (200 mL) were successively added <strong>[155377-05-2]methyl 6-trifluoromethyl-pyridine-2-carboxylate</strong> (10.0 g, 48.7 mmol) and biuret (4.2 g, 40.7 mmol). The reaction mixture was heated at reflux for 2 hours, and then cooled to room temperature. The reaction solution was concentrated in vacuo, and the resulting residue was poured into water, and adjusted to pH 7 with 6 mol/L HCl solution. After the resulting solid was filtered, the filter cake was washed with water, and then dried to afford 6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione (5.0 g, yield 47.5%).
47.5%	With sodium ethanolate; In ethanol; for 2h;Inert atmosphere; Reflux;	To a solution of sodium ethoxide (11.2 g, 165.0 mmol) in ethanol (200 mL) were added in sequence <strong>[155377-05-2]methyl 6-trifluoromethyl-pyridine-2-carboxylate</strong> (10.0 g, 48.7 mmol) and biuret (4.2 g, 40.7 mmol) under the protection of nitrogen gas. The mixture was heated to reflux for 2 hours and then cooled to room temperature. Then the reaction solution was concentrated under vacuum and reduced pressure, and the resulting residue was poured into water and adjusted to pH 7 with 6N hydrochloric acid solution. The resulting solid was filtered, and the filter cake was washed with water and then dried to afford the title compound (5.0 g, yield: 47.5%).

	With ethanol; sodium; for 1h;Reflux;	General procedure: Step 2: Preparation of 6-(6-trifluomethylpyridin-2-yl)-1,3,5-triazine-2,4-dione To a solution of freshly prepared NaOEt from Na (3.84 g, 0.16 mol, 3 eq) in ethanol (500 mL) was added methyl 6-trifluoromethylpicolinate (33 g, 0.16 mol, 3 eq) and biuret (5.3 g, 0.052 mol). The resulting mixture was heated to reflux for 1 hr and then concentrated. The residue was poured into water and treated with Sat. aq. NaHCO3 to adjust pH to 7. The precipitated solid was collected by filtration and dried under air to give the desired compound. 1H NMR (400 MHz, DMSO-d6): delta 10.88 (s, 1H), 8.46 (d, J=7.4 Hz, 1H), 8.28 (t, J=7.3 Hz, 1H), 8.11 (d, J=7.4 Hz, 1H). LC-MS: m/z 259 (M+H)+.
	With sodium ethanolate; In ethanol; for 1h;Reflux;	Step 2:Preparation of 6-(6- trfluomethylpyridin-2-yl)-1,3,5-triazine-2,4-dione. To a solution of freshly prepared NaOEt from Na (3.84 g, 0.16 mol, 3 eq) in ethanol (500 mL) was added methyl 6-trifluoromethylpicolinate (33 g, 0.16 mol, 3eq) and biuret (5.3 g, 0.052 mol). Theresultingmixture was heated to reflux for 1 hr and then concentrated. The residue was poured into water and treated with Sat. aq. NaHCO3 to adjust pH to 7. The precipitated solid was collected by filtration and dried under air to give the desired compound.?H NMR (400 MHz, DMSO-d6): 10.88 (s, 1H), 8.46 (d, J= 7.4 Hz, 1H), 8.28 (t, J 7.3 Hz, 1H), 8.11 (d, J= 7.4 Hz, 1H).LC-MS: m/z 259 (M+H).
		Sodium metal (13.46 g, 0.585 mol) is added to ethanol (1.35 L) and the mixture is stirred at room temperature until the sodium dissolves completely. To the resulting sodium ethoxide solution is added biuret (15.1 g, 0.146 mol) at 50C and the solution is stirred at 50 C for 10 min, followed by addition of <strong>[155377-05-2]6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester</strong> (90 g, 0.44 mol). The mixture is heated to reflux for 3 hours. The reaction mixture is concentrated and added to ice-water (1000 mL). Then concentrated HC1 (24.3 mL, 0.29 mol) is added to neutralize the mixture to a pH of between 7 and 8. The precipitated solid is collected by filtration and dried to give 6-(6-Trifluoromethyl -pyridin-2-yl)-lH-l ,3,5-triazine-2,4-dione, LCMS: m/z 259 (M+H)+.
	With sodium; In ethanol; at 50 - 80℃;Inert atmosphere;	1 L absolute ethanol is charged to the reaction vessel under N2 atmosphere and Sodium Metal (11.2 g, 0.488 mol) is added in portions under N2 atmosphere at below 50 C. The reaction is stirred for 5-10 minutes, then heated to 50-55 C. Dried Biuret (12.5 g, 0.122 mol) is added to the reaction vessel under N2 atmosphere at 50-55 C temperature, and stirred 10-15 minutes. While maintaining 50-55 C <strong>[155377-05-2]6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester</strong> (50.0 g, 0.244 mol) is added. The reaction mixture is heated to reflux (75-80 C) and maintained for 1.5-2 hours. Then cooled to 35-40 C, and concentrated at 45-50 C under vacuum. Water is added and the mixture is concentrated under vacuum then cooled to 35-40 C more water is added and the mixture cooled to 0 -5 C. pH is adjusted to 7-8 by slow addition of 6N HC1, and solid precipitated out and is centrifuged and rinsed with water and centrifuged again. The off white to light brown solid of 6-(6-Trifluoromethyl-pyridin-2-yl)-lH-l,3,5-triazine-2,4-dione is dried under vacuum for 8 to 10 hrs at 50 C to 60 C under 600mm/Hg pressure to provide 6-(6- Trifluoromethyl-pyridin-2-yl)- 1H- 1 ,3,5-triazine-2,4-dione.
		[00271j 1 L absolute ethanol is charged to the reaction vessel under N2 atmosphere and Sodium Metal (11.2 g, 0.488 mol) is added in portions under N2 atmosphere at below 50 C. The reaction is stirred for 5-10 minutes, then heated to 50-55 C. Dried Biuret (12.5 g, 0.122 mol) is added to the reaction vessel under N2 atmosphere at 50-55 C temperature, and stirred 10-15 minutes. While maintaining 50-55 C <strong>[155377-05-2]6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester</strong> (50.0 g, 0.244 mol) is added. The reaction mixture is heated to reflux (75-80 C) and maintained for 1.5-2 hours. Then cooled to 35-40 C, and concentrated at 45-50 C under vacuum. Water is added and the mixture is concentrated under vacuum then cooled to 35-40 C more water is added and the mixture cooled to 0 -5 C. pH is adjusted to 7-8 by slow addition of 6N HC1, and solid precipitated out and is centrifuged and rinsed with water and centrifuged again. The off white to light brown solid of 6-(6-Trifluoromethyl-pyridin-2-yl)- 1 H- 1,3,5 -triazine-2,4-dione is dried under vacuum for 8 to 10 hrs at 50 C to 60 C under 600mmlHg pressure to provide 6-(6- Trifluoromethyl-pyridin-2-yl)- 1 H- 1,3,5 -triazine-2,4-dione.
		1 L absolute ethanol is charged to the reaction vessel under N2 atmosphere and Sodium Metal (11.2 g, 0.488 mol) is added in portions under N2 atmosphere at below 50 C. The reaction is stirred for 5-10 minutes, then heated to 50-55 C. Dried Biuret (12.5 g, 0.122 mol) is added to the reaction vessel under N2 atmosphere at 50-55 C temperature, and stirred 10- 15 minutes. While maintaining 50-55 C <strong>[155377-05-2]6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester</strong> (50.0 g, 0.244 mol) is added. The reaction mixture is heated to reflux (75-80 C) and maintained for 1.5-2 hours. Then cooled to 35-40 C, and concentrated at 45-50 C under vacuum. Water is added and the mixture is concentrated under vacuum then cooled to 35-40 C more water is added and the mixture cooled to 0 -5 C. pH is adjusted to 7-8 by slow addition of 6N HC1, and solid precipitated out and is centrifuged and rinsed with water and centrifuged again. The off white to light brown solid of 6-(6-Trifluoromethyl-pyridin-2-yl)- lH-l,3,5-triazine-2,4-dione is dried under vacuum for 8 to 10 hrs at 50 C to 60 C under 600mm/Hg pressure to provide 6-(6-Trifluoromethyl-pyridin-2-yl)-lH-l,3,5-triazine-2,4- dione.
		1 L absolute ethanol was charged to the reaction vessel under N2 atmosphere and sodium metal (11.2 g, 0.488 mol) was added in portions under N2 atmosphere at below 50C. The reaction was stirred for 5-10 minutes, then heated to 50-55C. Dried Biuret (12.5 g,0.122 mol) was added to the reaction vessel under N2 atmosphere at 50-55C temperature, and stirred for 10-15 minutes. While maintaining 50-55C <strong>[155377-05-2]6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester</strong> (50.0 g, 0.244 mol) was added. The reaction mixture was heated to reflux (75- 80C) and maintained for 1.5-2 hours, then cooled to 35-40C, and concentrated at 45-50C under vacuum. Water was added and the mixture was concentrated under vacuum then cooled to 3 5-40 C, more water was added and the mixture was cooled to 0 -5C. pH was adjusted to 7-8 by slow addition of 6N HC1, a solid precipitated which was centrifuged and rinsed with water and centrifuged again. The off white to light brown solid of 6-(6-trifluoromethyl-pyridin-2-yl)- 1H-1,3,5-triazine-2,4-dione was dried under vacuum for 8 to 10 hrs at 50C to 60C under 600 mm/Hg pressure to provide 6-(6- trifluoromethyl-pyridin-2-yl)-1H- 1,3,5 -triazine-2,4-dione.
		1 L absolute ethanol was charged to the reaction vessel under N2 atmosphere and sodium metal (11.2 g, 0.488 mol) was added in portions under N2 atmosphere at below 50 C. The reaction was stirred for 5-10 minutes, then heated to 50-55 C. Dried Biuret (12.5 g, 0.122 mol) was added to the reaction vessel under N2 atmosphere at 50-55 C. temperature, and stirred for 10-15 minutes. While maintaining 50-55 C. <strong>[155377-05-2]6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester</strong> (50.0 g, 0.244 mol) was added. The reaction mixture was heated to reflux (75-80 C.) and maintained for 1.5-2 hours, then cooled to 35-40 C., and concentrated at 45-50 C. under vacuum. Water was added and the mixture was concentrated under vacuum then cooled to 35-40 C., more water was added and the mixture was cooled to 0-5 C. pH was adjusted to 7-8 by slow addition of 6N HCl, a solid precipitated which was centrifuged and rinsed with water and centrifuged again. The off white to light brown solid of 6-(6-trifluoromethyl-pyridin-2-yl)-1H-1,3,5-triazine-2,4-dione was dried under vacuum for 8 to 10 hrs at 50 C. to 60 C. under 600 mm/Hg pressure to provide 6-(6-trifluoromethyl-pyridin-2-yl)-1H-1,3,5-triazine-2,4-dione.
		Example 2, Step 3: Preparation of 6-(6-trifluoromethyl-pyridin-2-yl)-l H-1,3,5-triazine-2,4-dione 1 L absolute ethanol was charged to the reaction vessel under N2 atmosphere and sodium metal (11.2 g, 0.488 mol) was added in portions under N2 atmosphere at below 50 C. The reaction was stirred for 5-10 minutes, then heated to 50-55 C. Dried Biuret (12.5 g, 0.122 mol) was added to the reaction vessel under N2 atmosphere at 50-55 C. temperature, and stirred for 10-15 minutes. While maintaining 50-55 C. <strong>[155377-05-2]6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester</strong> (50.0 g, 0.244 mol) was added. The reaction mixture was heated to reflux (75-80 C.) and maintained for 1.5-2 hours, then cooled to 35-40 C., and concentrated at 45-50 C. under vacuum. Water was added and the mixture was concentrated under vacuum then cooled to 35-40 C., more water was added and the mixture was cooled to 0-5 C. pH was adjusted to 7-8 by slow addition of 6N HCl, a solid precipitated which was centrifuged and rinsed with water and centrifuged again. The off white to light brown solid of 6-(6-trifluoromethyl-pyridin-2-yl)-1H-1,3,5-triazine-2,4-dione was dried under vacuum for 8 to 10 hrs at 50 C. to 60 C. under 600 mm/Hg pressure to provide 6-(6-trifluoromethyl-pyridin-2-yl)-1H-1,3,5-triazine-2,4-dione.
		The biuret (13 g, 126.3 mmol) was dissolved in 300 mL of ethylene glycol dimethyl ether.Sodium hydride (42 g, 1053 mmol) was added portionwise and stirred at 50 C for 1 h.Add 6-(trifluoromethyl)-picolinic acid methyl ester (21.6 g, 105.3 mmol),The reaction was heated at 85 C for 16 h. The reaction solution was poured into water, and the pH was adjusted with concentrated hydrochloric acid.Filtration and drying of the filter cake gave the title compound.
		Biuret (13 g, 126.3 mmol) was dissolved in 300 mL of ethylene glycol dimethyl ether, and sodium hydride (42 g, 1053 mmol) was added in batches. The mixture was stirred at 50 C for 1 h. Methyl 6-(trifluoromethyl)picolinate (21.6 g, 105.3 mmol) was added and the mixture was heated at 85 C for 16 h. The resultant solution was poured into water, and the pH was adjusted with concentrated hydrochloric acid. The resultant was filtered, and the filter cake was dried to give the title compound.
		The biuret (13 g, 126.3 mmol) was dissolved in 300 mL of ethylene glycol dimethyl ether.Sodium hydride (42 g, 1053 mmol) was added portionwise.Stir at 50 C for 1 h.Methyl 6-(trifluoromethyl)-picolinate (21.6 g, 105.3 mmol) was added and the mixture was heated at 85 C for 16 h. The reaction solution was poured into water, and the pH was adjusted with concentrated hydrochloric acid.Filter, filter cake to dry,The title compound was obtained.
	With sodium hydride; In 1,2-dimethoxyethane; mineral oil; at 50 - 85℃; for 16h;	The biuret (13 g, 126.3 mmol) was dissolved in 300 mL of ethylene glycol dimethyl ether.Sodium hydride (42 g, 1053 mmol) was added portionwise and stirred at 50 C for 1 h.Add 6-(trifluoromethyl)-picolinic acid methyl ester (21.6 g, 105.3 mmol),heatingThe reaction was carried out at 85 C for 16 h.The reaction solution was poured into water, the pH was adjusted with concentrated hydrochloric acid, filtered, and the filter cake was dried.The title compound was obtained.
		The biuret (13 g, 126.3 mmol) was dissolved in 300 mL of ethylene glycol dimethyl ether, sodium hydride (42 g, 1053 mmol) was added portionwise, and stirred at 50 C for 1 h. Methyl 6-(trifluoromethyl)-picolinate (21.6 g, 105.3 mmol) was added and the mixture was heated at 85 C for 16 h. The reaction solution was poured into water, the pH was adjusted with concentrated hydrochloric acid, filtered, and then filtered to give the title compound.
	With sodium hydride; In 1,2-dimethoxyethane; at 50 - 85℃; for 16h;	The biuret (13 g, 126.3 mmol) was dissolved in 300 mL of ethylene glycol dimethyl ether, sodium hydride (42 g, 1053 mmol) was added portionwise, and stirred at 50 C for 1 h. Methyl 6-(trifluoromethyl)-picolinate (21.6 g, 105.3 mmol) was added and the mixture was heated at 85 C for 16 h. The reaction solution was poured into water, the pH was adjusted with concentrated hydrochloric acid, filtered, and then filtered to give the title compound.

References: [1]Patent: WO2017/24134,2017,A1 .Location in patent: Paragraph 0073; 0075; 0079; 0080; 0082.
[2]Patent: EP3330258,2018,A1 .Location in patent: Paragraph 0079-0080.
[3]Patent: US2019/352281,2019,A1 .Location in patent: Paragraph 0185; 0188; 0189.
[4]Patent: US2015/18328,2015,A1 .Location in patent: Paragraph 0722-0723.
[5]Patent: WO2015/3640,2015,A1 .Location in patent: Page/Page column 156; 157.
[6]Patent: WO2015/18060,2015,A1 .Location in patent: Page/Page column 48-49.
[7]Patent: WO2015/17821,2015,A2 .Location in patent: Page/Page column 67; 68.
[8]Patent: WO2016/53850,2016,A1 .Location in patent: Paragraph 00271; 00278.
[9]Patent: WO2016/126798,2016,A1 .Location in patent: Page/Page column 73.
[10]Patent: WO2017/66611,2017,A1 .Location in patent: Paragraph 0561.
[11]Patent: US2018/64715,2018,A1 .Location in patent: Paragraph 0206.
[12]Patent: US2018/311249,2018,A1 .Location in patent: Paragraph 0345.
[13]Patent: CN109265444,2019,A .Location in patent: Paragraph 0051; 0056; 0057; 0058.
[14]Patent: EP3489230,2019,A1 .Location in patent: Paragraph 0065; 0068; 0069.
[15]Patent: CN110054615,2019,A .Location in patent: Paragraph 0104; 0109-0111.
[16]Patent: CN110054616,2019,A .Location in patent: Paragraph 0068; 0073-0075.
[17]Patent: CN110054617,2019,A .Location in patent: Paragraph 0036; 0041-0043.
[18]Patent: CN110054614,2019,A .Location in patent: Paragraph 0079; 0084-0086.

20
[ 155377-05-2 ]
C₁₆H₁₀ClF₅N₆ [ No CAS ]

References: [1]Patent: US2015/18328,2015,A1 .
[2]Patent: WO2015/3640,2015,A1 .

21
[ 155377-05-2 ]
N²-(3,3-difluorocyclopentyl)-N⁴-(2-(1,1-difluoroethyl)pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine [ No CAS ]

References: [1]Patent: US2015/18328,2015,A1 .
[2]Patent: WO2015/3640,2015,A1 .

22
[ 155377-05-2 ]
N2,N4-bis ((1S,3S)-3-(4-fluorophenyl)cyclobutyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine [ No CAS ]

References: [1]Patent: WO2015/3640,2015,A1 .

23
[ 67-56-1 ]
[ 131747-42-7 ]
[ 155377-05-2 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; for 2h;Reflux;	To a solution of 6-trifluoromethyl-pyridine-2-carboxylic acid (300 g, 1.57 mol) in methanol (2.25 L) is added SOCl2 (225 g, 1.88 mol) dropwise at room temperature, while maintaining room temperature. After addition, the mixture is heated to reflux and stirred for two hours then concentrated to remove the solvent. The crude product is diluted with ethyl acetate and washed with saturated NaHC03 solution. The organic layer is dried over anhydrous Na2SC>4 and concentrated to give 6-trifluoromethyl- pyridine-2-carboxylic acid methyl ester, LCMS: m z 206 (M+H)+.
	With acetyl chloride; at 65 - 70℃;Inert atmosphere;	[00270j Methanol is added to the reaction vessel under nitrogen atmosphere. 6- trifluoromethyl-pyridine-2-carboxylic acid (150 g, 0.785 mol) is added and dissolved at ambient temperature. Acetyl chloride (67.78 g, 0.863 mol) is added dropwise at a temperature below 45C. The reaction mixture is maintained at 65-70 C for about 2-2.5 h, and then concentrated at35-45 C under vacuum and cooled to 25-35 C. The mixture is diluted with ethyl acetate and rinsed with saturated NaHCO3 solution then rinsed with brine solution. The mixture is concentrated at temp 35-45 C under vacuum and cooled to 25-35 C, then rinsed with n-heptane and concentrated at temp 35-45 C under vacuum, then degassed to obtain brown solid, which is rinsed with n-heptane and stirred for 10-15 minute at 25-35 C. The suspension is cooled to -40 to -30 C while stirring, and filtered and dried to provide 6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester.
	With acetyl chloride; at 45 - 70℃;Inert atmosphere;	Example 1, Step 2: preparation of 6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester Methanol is added to the reaction vessel under nitrogen atmosphere. 6-trifluoromethyl- pyridine-2-carboxylic acid (150 g, 0.785 mol) is added and dissolved at ambient temperature. Acetyl chloride (67.78 g, 0.863 mol) is added dropwise at a temperature below 45 C. The reaction mixture is maintained at 65-70 C for about 2-2.5 h, and then concentrated at 35-45 C under vacuum and cooled to 25-35 C. The mixture is diluted with ethyl acetate and rinsed with saturated NaHC03 solution then rinsed with brine solution. The mixture is concentrated at temp 35-45 C under vacuum and cooled to 25-35 C, then rinsed with n- heptane and concentrated at temp 35-45 C under vacuum, then degassed to obtain brown solid, which is rinsed with n-heptane and stirred for 10-15 minute at 25-35 C. The suspension is cooled to -40 to -30 C while stirring, and filtered and dried to provide 6- trifluoromethyl-pyridine-2-carboxylic acid methyl ester.

	With hydrogenchloride; In water; at 80℃; for 48h;	To a solution of 6-trifluoromethyl-pyridine-2-carboxylic acid in methanol (770 ml) was added concentrated HC1 (6 ml). The mixture was stirred at 80C for 48 hours then concentrated to remove the volatile.The crude product was diluted with ethyl acetated and washed with Sat. NaHCO3 solution. Theorganic layer was dried with anhydrous Na2504 and concentrated to give6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (10) as a white solid. LC-MS: m/z 206(M+H).
	With acetyl chloride; at 45 - 70℃;Inert atmosphere;	Methanol was added to the reaction vessel under nitrogen atmosphere. 6-trifluoromethyl-pyridine-2-carboxylic acid (150 g, 0.785 mol) was added and dissolved at ambient temperature. Acetyl chloride (67.78 g, 0.863 mol) was added dropwise at a temperature below 45C. The reaction mixture was maintained at 65-70C for about 2-2.5 h, and then concentrated at 3 5-45C under vacuum and cooled to 25-35C. The mixture was diluted with ethyl acetate and rinsed with saturated NaHCO3 solution then rinsed with brine solution. The mixture was concentrated at 3 5-45C under vacuum and cooled to 25-35C, then rinsed with nheptane and concentrated at 3 5-45C under vacuum, then degassed to obtain brown solid, which was rinsed with n-heptane and stirred for 10-15 minute at 25-35C. The suspension was cooled to -40 to -3 0C while stirring, and filtered and dried to provide 6-trifluoromethyl-pyridine-2- carboxylic acid methyl ester.
21 g	With sulfuric acid; for 14h;Reflux;	To a solution of 6-trifluoromethyl-pyridine-2-carboxylic acid (22 g, 1 equiv.) in methanol (200 mL) was added concentrated H2S04 (0.3 mL). The mixture was stirred at reflux for 14 hours and then cooled to ambient. Solid NaHCO3 (10 g) was added and the suspension was stirred for 30 minutes. The mixture was filtered and the filtrate was concentrated to remove the volatile. The crude product was diluted with ethyl acetated (200 mL) and dried with anhydrous Na2504. The mixture was filtered and concentrated to give 6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (2) as a waxy solid (21 g).
	With acetyl chloride; at 45 - 70℃;Inert atmosphere;	Methanol was added to the reaction vessel under nitrogen atmosphere. 6-trifluoromethyl-pyridine-2-carboxylic acid (150 g, 0.785 mol) was added and dissolved at ambient temperature. Acetyl chloride (67.78 g, 0.863 mol) was added dropwise at a temperature below 45 C. The reaction mixture was maintained at 65-70 C. for about 2-2.5 h, and then concentrated at 35-45 C. under vacuum and cooled to 25-35 C. The mixture was diluted with ethyl acetate and rinsed with saturated NaHC03 solution then rinsed with brine solution. The mixture was concentrated at 35-45 C. under vacuum and cooled to 25-35 C., then rinsed with n-heptane and concentrated at 35-45 C. under vacuum, then degassed to obtain brown solid, which was rinsed with n-heptane and stirred for 10-15 minute at 25-35 C. The suspension was cooled to -40 to -30 C. while stirring, and filtered and dried to provide 6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester.
	With sulfuric acid; at 65℃; for 10h;	[1344] to a solution of 6-(trifluoromethyl)picolinic acid (10 g, 52.33 mmol) in MeOH (150 ml) was added H2SO4 (1.03 g, 10.47 mmol, 557.88 ul) dropwise. After stirred at 65 C for 10 hours, the mixture was cooled to room temperature, neutralized with a saturated aqueous NaHCO3 solution, and extracted with ch2c12 (70 ml x 3). The organic phases were combined, dried with anhydrous Na2SO4, and evaporated to afford crude intermediate compound 287a (9.20 g, 85.71% yield) as white solid. 1H NMR (400 mhz, CDCl3) delta 8.32 (d, = 8.0 hz, 1h), 8.09 - 8.05 (m, 1h), 7.88 (d, = 8.0 hz, 1h), 4.03 (s, 3h).
	With acetyl chloride; at 45 - 70℃;Inert atmosphere;	Example 2, Step 2: Preparation of 6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester Methanol was added to the reaction vessel under nitrogen atmosphere. 6-trifluoromethyl-pyridine-2-carboxylic acid (150 g, 0.785 mol) was added and dissolved at ambient temperature. Acetyl chloride (67.78 g, 0.863 mol) was added dropwise at a temperature below 45 C. The reaction mixture was maintained at 65-70 C. for about 2-2.5 h, and then concentrated at 35-45 C. under vacuum and cooled to 25-35 C. The mixture was diluted with ethyl acetate and rinsed with saturated NaHCO3 solution then rinsed with brine solution. The mixture was concentrated at 35-45 C. under vacuum and cooled to 25-35 C., then rinsed with n-heptane and concentrated at 35-45 C. under vacuum, then degassed to obtain brown solid, which was rinsed with n-heptane and stirred for 10-15 minute at 25-35 C. The suspension was cooled to -40 to -30 C. while stirring, and filtered and dried to provide 6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester.
	With thionyl chloride; for 12h;Reflux;	6-Trifluoromethylpyridine-2-carboxylic acid (25 g, 130.8 mmol) was dissolved in 300 mL of methanol.Thionyl chloride(23.3 g, 196.2 mmol), the mixture was heated and refluxed for 12 h. The reaction solution is concentrated and dried.Add saturated sodium bicarbonate solution to adjust the pH, and extract with ethyl acetate.Dry over anhydrous sodium sulfate and concentrate to give the title compound.
	With thionyl chloride; for 12h;Reflux;	6-Trifluoromethylpyridine-2-carboxylic acid (25 g, 130.8 mmol) was dissolved in 300 mL of methanol, and thionyl chloride (23.3 g, 196.2 mmol) was added dropwise. After addition, the mixture was refluxed for reaction for 12 h. The resultant solution was concentrated untill dry, and saturated sodium hydrogen carbonate solution was added to adjust the pH, and then the resultant was extracted with ethyl acetate, dried over anhydrous sodium sulfate to give the title compound.
	With thionyl chloride; for 12h;Reflux;	6-trifluoromethylpyridine-2-carboxylic acid(25g, 130.8mmol) dissolved in 300mL of methanol,Thionyl chloride (23.3 g, 196.2 mmol) was added dropwise.The mixture was heated to reflux for 12 h. The reaction solution is concentrated and dried.Add saturated sodium bicarbonate solution to adjust the pH,Extracted with ethyl acetate and dried over anhydrous sodium sulfate.Concentrated to give the title compound.
	With thionyl chloride; for 12h;Reflux;	6-Trifluoromethylpyridine-2-carboxylic acid (25 g, 130.8 mmol) was dissolved in 300 mL of methanol, and thionyl chloride (23.3 g, 196.2 mmol) was added dropwise, and the mixture was refluxed for 12 h. The reaction solution is concentrated and dried.Add the saturated sodium bicarbonate solution to adjust the pH, extract with ethyl acetate and dry over anhydrous sodium sulfate.Concentrated to give the title compound.
	With thionyl chloride; at 12℃;Reflux;	6-Trifluoromethylpyridine-2-carboxylic acid (25 g, 130.8 mmol) was dissolved in 300 mL of methanol.Thionyl chloride (23.3 g, 196.2 mmol) was added dropwise, and the mixture was heated under reflux for 12 h.The reaction mixture was concentrated to dryness.ConcentratedTitle compound.
	With thionyl chloride; for 12h;Reflux;	6-Trifluoromethylpyridine-2-carboxylic acid (25 g, 130.8 mmol) was dissolved in 300 mL of methanol, and thionyl chloride (23.3 g, 196.2 mmol) was added dropwise, and the mixture was refluxed for 12 h. The reaction mixture was concentrated to dryness.

References: [1]Patent: WO2015/18060,2015,A1 .Location in patent: Page/Page column 48.
[2]Patent: WO2015/17821,2015,A2 .Location in patent: Page/Page column 67.
[3]Patent: WO2016/53850,2016,A1 .Location in patent: Paragraph 00270; 00277.
[4]Patent: WO2016/126798,2016,A1 .Location in patent: Page/Page column 72; 73.
[5]Patent: WO2017/24134,2017,A1 .Location in patent: Paragraph 0073; 0074.
[6]Patent: WO2017/66611,2017,A1 .Location in patent: Paragraph 0560.
[7]Patent: WO2017/69878,2017,A1 .Location in patent: Paragraph 00104; 00105.
[8]Patent: US2018/64715,2018,A1 .Location in patent: Paragraph 0205.
[9]Patent: WO2018/64119,2018,A1 .Location in patent: Paragraph 1344.
[10]Patent: US2018/311249,2018,A1 .Location in patent: Paragraph 0344.
[11]Patent: CN109265444,2019,A .Location in patent: Paragraph 0051; 0052; 0053; 0054; 0055.
[12]Patent: EP3489230,2019,A1 .Location in patent: Paragraph 0065; 0066; 0067.
[13]Patent: CN110054615,2019,A .Location in patent: Paragraph 0104; 0106-0108.
[14]Patent: CN110054614,2019,A .Location in patent: Paragraph 0079-0083.
[15]Patent: CN110054616,2019,A .Location in patent: Paragraph 0068-0072.
[16]Patent: CN110054617,2019,A .Location in patent: Paragraph 0036; 0038-0040.

24
[ 155377-05-2 ]
[ 1446502-11-9 ]

25
[ 155377-05-2 ]
[ 1446507-68-1 ]

References: [1]Patent: WO2015/18060,2015,A1 .
[2]Patent: WO2015/17821,2015,A2 .
[3]Patent: WO2016/53850,2016,A1 .
[4]Patent: WO2016/126798,2016,A1 .
[5]Patent: WO2017/24134,2017,A1 .
[6]Patent: WO2017/66611,2017,A1 .
[7]Patent: WO2017/69878,2017,A1 .
[8]Patent: EP3330258,2018,A1 .
[9]Patent: US2018/64715,2018,A1 .
[10]Patent: US2018/311249,2018,A1 .
[11]Patent: CN109265444,2019,A .
[12]Patent: EP3489230,2019,A1 .
[13]Patent: CN110054615,2019,A .
[14]Patent: CN110054614,2019,A .
[15]Patent: CN110054617,2019,A .
[16]Patent: US2019/352281,2019,A1 .

26
[ 155377-05-2 ]
2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate [ No CAS ]

References: [1]Patent: WO2015/18060,2015,A1 .
[2]Patent: WO2015/17821,2015,A2 .
[3]Patent: US2018/311249,2018,A1 .

27
[ 155377-05-2 ]
tert-butyl 3-(6-(trifluoromethyl)pyridin-2-yl)-5,6-dihydro-[1,2,4]-triazolo[4,3-a]pyrazine-7(8H)-carboxylate [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3060 - 3082.

28
[ 155377-05-2 ]
[ 1338372-54-5 ]

References: [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3060 - 3082.

29
[ 155377-05-2 ]
3-(6-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]-triazolo[4,3-a]pyrazine dihydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3060 - 3082.

30
[ 155377-05-2 ]
[ 883037-22-7 ]

References: [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3060 - 3082.

31
[ 26218-75-7 ]
1,10-phenanthroline trifluoroacetic acid cuprous (I) [ No CAS ]
[ 155377-05-2 ]

References: [1]Chemistry - A European Journal,2016,vol. 22,p. 2075 - 2084.

32
[ 155377-05-2 ]
2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate [ No CAS ]

References: [1]Patent: WO2016/53850,2016,A1 .
[2]Patent: US2018/64715,2018,A1 .

33
[ 26218-75-7 ]
[(2,2'-bipyridine)₂Cu][O₂CCF₂Cl] [ No CAS ]
[ 155377-05-2 ]

References: [1]RSC Advances,2016,vol. 6,p. 75465 - 75469.

34
[ 155377-05-2 ]
2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino] propan-2-ol methanesulfonate [ No CAS ]

References: [1]Patent: WO2016/126798,2016,A1 .
[2]Patent: WO2017/66611,2017,A1 .

35
[ 155377-05-2 ]
[ 1446507-48-7 ]

References: [1]Patent: WO2017/24134,2017,A1 .

Historical Records

Technical Information

• Acyl Group Substitution • Alkyl Halide Occurrence • Bouveault-Blanc Reduction • Catalytic Hydrogenation • Complex Metal Hydride Reductions • Ester Cleavage • Preparation of Amines • Reactions with Organometallic Reagents • Specialized Acylation Reagents-Carbodiimides and Related Reagents

Related Functional Groups of
[ 155377-05-2 ]

Fluorinated Building Blocks

A546612 [1209248-98-5]

Methyl 6-(fluoromethyl)picolinate

Similarity: 0.93

A689990 [1214330-74-1]

3-Methoxy-6-(trifluoromethyl)picolinic acid

Similarity: 0.86

A274794 [1211538-62-3]

Methyl 3-bromo-6-(trifluoromethyl)picolinate

Similarity: 0.84

A183116 [1245647-61-3]

Methyl 5-fluoro-6-methylpicolinate

Similarity: 0.82

A248286 [455941-78-3]

Methyl 4-(trifluoromethyl)picolinate

Similarity: 0.79

Esters

A546612 [1209248-98-5]

Methyl 6-(fluoromethyl)picolinate

Similarity: 0.93

A274794 [1211538-62-3]

Methyl 3-bromo-6-(trifluoromethyl)picolinate

Similarity: 0.84

A441856 [13602-11-4]

Methyl 6-methylpyridine-2-carboxylate

Similarity: 0.83

A183116 [1245647-61-3]

Methyl 5-fluoro-6-methylpicolinate

Similarity: 0.82

A164550 [69950-65-8]

Methyl 6-formyl-2-pyridinecarboxylate

Similarity: 0.79

Trifluoromethyls

A689990 [1214330-74-1]

3-Methoxy-6-(trifluoromethyl)picolinic acid

Similarity: 0.86

A274794 [1211538-62-3]

Methyl 3-bromo-6-(trifluoromethyl)picolinate

Similarity: 0.84

A248286 [455941-78-3]

Methyl 4-(trifluoromethyl)picolinate

Similarity: 0.79

A201783 [131747-53-0]

(6-(Trifluoromethyl)pyridin-2-yl)methanol

Similarity: 0.77

A882088 [128072-94-6]

Ethyl 5-(trifluoromethyl)-2-pyridinecarboxylate

Similarity: 0.75

Related Parent Nucleus of
[ 155377-05-2 ]

Pyridines

A546612 [1209248-98-5]

Methyl 6-(fluoromethyl)picolinate

Similarity: 0.93

A689990 [1214330-74-1]

3-Methoxy-6-(trifluoromethyl)picolinic acid

Similarity: 0.86

A274794 [1211538-62-3]

Methyl 3-bromo-6-(trifluoromethyl)picolinate

Similarity: 0.84

A441856 [13602-11-4]

Methyl 6-methylpyridine-2-carboxylate

Similarity: 0.83

A183116 [1245647-61-3]

Methyl 5-fluoro-6-methylpicolinate

Similarity: 0.82

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

{[proInfo.proName]}

CAS No.: 155377-05-2

{[proInfo.proName]}

CAS No.: 155377-05-2

Alternative Products

Product Details of [ 155377-05-2 ]

Safety of [ 155377-05-2 ]

Computational Chemistry of [ 155377-05-2 ] Show Less

Physicochemical Properties

Lipophilicity

Water Solubility

Pharmacokinetics

Druglikeness

Medicinal Chemistry

Application In Synthesis of [ 155377-05-2 ]

[ 155377-05-2 ] Synthesis Path-Downstream 1~35

Related Products

Historical Records

Technical Information

Categories

Related Functional Groups of
[ 155377-05-2 ]

Fluorinated Building Blocks

Esters

Trifluoromethyls

Related Parent Nucleus of
[ 155377-05-2 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Molarity Calculator

Total Compounds Calculator

Dissolution Calculator

{[proInfo.proName]}

CAS No.: 155377-05-2

{[proInfo.proName]}

CAS No.: 155377-05-2

Alternative Products

Product Details of [ 155377-05-2 ]

Safety of [ 155377-05-2 ]

Computational Chemistry of [ 155377-05-2 ] Show Less

Physicochemical Properties

Lipophilicity

Water Solubility

Pharmacokinetics

Druglikeness

Medicinal Chemistry

Application In Synthesis of [ 155377-05-2 ]

[ 155377-05-2 ] Synthesis Path-Downstream 1~35

Related Products

Historical Records

Technical Information

Categories

Related Functional Groups of [ 155377-05-2 ]

Fluorinated Building Blocks

Esters

Trifluoromethyls

Related Parent Nucleus of [ 155377-05-2 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Molarity Calculator

Total Compounds Calculator

Dissolution Calculator

Related Functional Groups of
[ 155377-05-2 ]

Related Parent Nucleus of
[ 155377-05-2 ]