823221-93-8|5-Bromo-2-chloro-4-(trifluoromethyl)pyridine| Ambeed

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Quality Control of [ 823221-93-8 ] Purity: 95% SDS Specification

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Product Details of [ 823221-93-8 ]

CAS No. :	823221-93-8
Formula :	C₆H₂BrClF₃N
M.W :	260.44
SMILES Code :	FC(C1=CC(Cl)=NC=C1Br)(F)F
MDL No. :	MFCD11100520
InChI Key :	SYBSBIJPNQAETE-UHFFFAOYSA-N
Pubchem ID :	37859478

Safety of [ 823221-93-8 ]

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

Computational Chemistry of [ 823221-93-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.17
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	41.95
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	12.89 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.1
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	3.39
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	4.67
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.	2.9
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	3.72
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.36

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.89
Solubility	0.0332 mg/ml ; 0.000128 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.	-3.34
Solubility	0.119 mg/ml ; 0.000457 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	-4.38
Solubility	0.0108 mg/ml ; 0.0000414 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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.	-5.48 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	1.0
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	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.77

Application In Synthesis of [ 823221-93-8 ]

* 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 [ 823221-93-8 ]

[ 823221-93-8 ] Synthesis Path-Downstream 1~35

1
[ 124-38-9 ]
[ 823221-93-8 ]
6-chloro-4-(trifluoromethyl)pyridine-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66.6%		To a solution of butyl magnesium chloride (27.8mL, 47.2mmol, 0.7eq, 1.7 M in THF) in THF was added butyl lithium (30.0mL, 74.3mmol, l. leq, 2.5M in hexane) at 0C and the reaction mixture was stirred for 10 min, then diluted with THF (80mL) and cooled to -78C. Then, <strong>[823221-93-8]5-bromo-2-chloro-4-(trifluoromethyl)pyridine</strong> (17.5g, 67.5mmol, leqm procedure described in Example 93) in THF (30mL) was added and the reaction mixture was stirred for lh at same temperature, before being poured onto crushed dry ice then slowly allowed to warm to RT for 16h. TLC indicated polar spot and the reaction mixture was concentrated and acidified with 2N HC1 (80mL) and extracted with EtOAc (2X 500mL). The organic layer was separated, dried with sodium sulfate and concentrated under reduced pressure to give crude residue. The crude compound was recrystallized from n-pentane (30mL) and dried using high vacuum to give 6-chloro-4-(trifluoromethyl)nicotinic acid (lOg, 66.6%) as an off white solid compound. LCMS: [M+H]+ 224.05.
53.8%		A stirred solution of 20% n-butyl magnesium chloride (63 mL, 127.2 mmol, 1.1 eq) in THF (50 mL) was cooled to 0 C and n-butyl lithium (48 mL, 115.8 mmol, le q, 2.5M in hexane) was added. The resulting reaction mixture was stirred for 10 mm, then diluted with THF (100 mL), cooled to -78 C and a solution of <strong>[823221-93-8]5-bromo-2-chloro-4-(trifluoromethyl)pyridine</strong> (30 g, 115.8 mmol, 1 eq) in THF (50 mL) was added. The reaction mixture was stirred for lh at -78 C. The mixture was quenched with crushed dry ice and allowed to warm to RT and stirred for 16 h. TLC analysis indicated the formation of a polar spot. The reaction mixture was concentrated, acidified with 2N HC1 (80 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was recrystallized from n-pentane (30 mL) and dried on high vacuum to give 6-chloro-4-(trifluoromethyl)nicotinic acid (14 g, 53.8% yield) as off white solid. LCMS: [M+Hj 226.29.

References: [1]Tetrahedron,2004,vol. 60,p. 11869 - 11874.
[2]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00264.
[3]Patent: WO2019/46944,2019,A1 .Location in patent: Paragraph 00163.

2
[ 81290-20-2 ]
[ 401892-47-5 ]
[ 823221-93-8 ]

References: [1]Tetrahedron,2004,vol. 60,p. 11869 - 11874.

3
[ 823221-93-8 ]
[ 823221-94-9 ]

References: [1]Tetrahedron,2004,vol. 60,p. 11869 - 11874.

4
[ 53939-30-3 ]
[ 823221-93-8 ]

References: [1]Tetrahedron,2004,vol. 60,p. 11869 - 11874.
[2]Patent: WO2017/147701,2017,A1 .
[3]Patent: WO2017/147700,2017,A1 .
[4]Patent: WO2019/46944,2019,A1 .

5
[ 823221-93-8 ]
[ 823222-00-0 ]

References: [1]Tetrahedron,2004,vol. 60,p. 11869 - 11874.

6
[ 111-49-9 ]
[ 823221-93-8 ]
C₁₂H₁₄BrF₃N₂ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6578 - 6581.

7
[ 109919-32-6 ]
[ 823221-93-8 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6578 - 6581.

8
[ 823221-93-8 ]
[ 1443792-54-8 ]

Yield	Reaction Conditions	Operation in experiment
40%	With acetyl chloride; sodium iodide; In acetonitrile; at 40℃; for 1.5h;	[006521 Prepared using General Procedure 17. To a stirred a solution of 5-bromo-2- chloro-4-(trifluoromethyl)pyridine (150 mg, 0.576 mmol) in acetonitrile (2 mL) was added sodium iodide (518 mg, 3.45 mrnol). The reaction mixture was heated to 40C and acetyl chloride (26.0 mg, 0.345 mmol) was added. The reaction mixture was stirred at 40C for 90 mm. Once cooled, the reaction was quenched with NaHCO3 (5 mL) and extracted with EA (3 x 5 mL). The combined organics were washed with brine (10 mL), dried over MgSO4and concentrated to give 80.0 mg (40%) of 5-brorno-2-iodo-4- (trifluoromethyl)pyridine as a white crystalline solid which was used in the subsequent step without purification. LCMS-ESI (rnIz) calculated for C6H2BrFLN: 351.9; found 352.5 [M+H], tR = 3.91 mm. (Method 1).
	With acetyl chloride; sodium iodide; In acetonitrile; at 40℃; for 1.5h;	Prepared using General Procedure 17: To a stirred a solution of 5- bromo-2-chloro-4-(trifluoromethyl)pyridine (150 mg, 0.576 mmol) in acetonitrile (2 mL) was added sodium iodide (518 mg, 3.45 mmol). The reaction mixture was heated to 40C and acetyl chloride (26.0 mg, 0.345 mmol) was added. The reaction mixture was stirred at 40C for 90 min. Once cooled, the reaction was quenched with NaHC03 (5 mL) and extracted with EA (3 x 5 mL). The combined organics were washed with brine (10 mL), dried over MgS04 and concentrated to give 80.0 mg (40%) of 5-bromo- 2-iodo-4-(trifluoromethyl)pyridine as a white crystalline solid which was used in the subsequent step without purification. LCMS-ESI (m/z) calculated for C6H2BrF3IN: 351.9; found 352.5 [M+H]+, tR = 3.91 min. (Method 1).

References: [1]Patent: WO2016/94729,2016,A1 .Location in patent: Paragraph 00652.
[2]Patent: WO2013/90454,2013,A2 .Location in patent: Paragraph 00393.

9
[ 823221-93-8 ]
5-bromo-2-methanesulfonyl-4-trifluoromethylpyridine [ No CAS ]

References: [1]Patent: WO2015/22073,2015,A1 .
[2]Patent: EP3489235,2019,A1 .

10
[ 5188-07-8 ]
[ 823221-93-8 ]
5-bromo-2-methylsulfanyl-4-trifluoromethylpyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	In 1,4-dioxane; for 14h;Reflux;	Step 1 : A mixture of <strong>[823221-93-8]5-bromo-2-chloro-4-trifluoromethyl-pyridine</strong> (1.0 g, 3.8 mmol) and sodium thio- methoxide (400 mg, 5.79 mmol) in dioxane (15 mL) was heated at reflux for 14 h. The RM was concentrated under reduced pressure and diluted with EtOAc and subsequently washed with water and brine (60 mL). The organic layer was dried and concentrated under reduced pressure to give the crude product which was purified by CC (Si02, EtOAc Hex) to yield the desired compound (800 mg, 77%).

References: [1]Patent: WO2015/22073,2015,A1 .Location in patent: Page/Page column 92.

11
[ 754-10-9 ]
[ 823221-93-8 ]
N-[6-chloro-4-(trifluoromethyl)-3-pyridyl]-2,2-dimethyl-propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With methanesulfonic acid(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II); potassium carbonate; In 1,4-dioxane; at 90 - 110℃; for 2.5h;	Procedure for synthesis of N-[6-chloro-4-(trifluoromethyl)-3-pyridyl]-2,2-dimethyl- propanamide (Step 1) A mixture of <strong>[823221-93-8]5-bromo-2-chloro-4-(trifluoromethyl)pyridine</strong> (commercially available) (75 mg, 0.288 mmol), 2,2-dimethylpropanamide (32 mg, 0.317 mmol), XantPhos Pd G3 precatalyst (13 mg, - - 0.014 mmol), K2C03 (79 mg, 0.57 mmol) in 1 ,4-Dioxane (0.5 ml.) was heated at 90C for 0.5h and then 1 10C for 2h. Purification by reverse phase HPLC delivered product (14 mg, 15%). LC-MS: (positive ES MH+ 281 ).
15%	With XantPhos Pd G3 precatalyst; potassium carbonate; In 1,4-dioxane; at 90 - 110℃; for 2.5h;	A mixture of <strong>[823221-93-8]5-bromo-2-chloro-4-(trifluoromethyl)pyridine</strong> (commercially available) (75 mg, 0.288mmol), 2,2-dimethylpropanamide (32 mg, 0.317 mmol), XantPhos Pd G3 precatalyst (13 mg,0.0 14 mmol), K2C03 (79 mg, 0.57 mmol) in 1 ,4-Dioxane (0.5 mL) was heated at 90C for 0.5hand then 110C for 2h. Purification by reverse phase HPLC delivered product (14 mg, 15%). LC-MS: (positive ES MH+ 281).

References: [1]Patent: WO2015/52076,2015,A1 .Location in patent: Page/Page column 103.
[2]Patent: WO2015/59262,2015,A1 .Location in patent: Page/Page column 59; 60.

12
[ 124-41-4 ]
[ 823221-93-8 ]
[ 688047-09-8 ]

Yield	Reaction Conditions	Operation in experiment
68%	In methanol; for 2h;Reflux;	To a solution of <strong>[823221-93-8]5-bromo-2-chloro-4-trifluoromethyl-pyridine</strong> (2.54 g, 9.80 mmol) in MeOH (25 mL) was added 25% NaOMe in MeOH (3.2 ml, 14.70 mmol) and heated at reflux for 2 h. The RM was diluted with water and extracted with hexane. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure to give 5-bromo-2-methoxy-4-trifluoromethyl-pyridine(1.7 g, 68%).
63.47%	In methanol; at 70℃; for 6h;	To a solution of <strong>[823221-93-8]5-bromo-2-chloro-4-(trifluoromethyl)pyridine</strong> (24.0 g, 93.02 mmol, 1.0 eq) in methanol (200 mL), was added 30% NaOMe (33.08 mL, 186.04 mmol, 2.0 eq). Then, the reaction mixture was heated at 70C for 6 h. TLC analysis indicated formation of a non-polar spot. The reaction mixture was diluted with water and extracted with EtOAc (3 X 200mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure at 30C. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) using 5% EtOAc in pet ether as an eluent to give 5-bromo-2-methoxy-4-(trifluoromethyl)pyridine (15g, 63.47%) as an off white solid. TLC: 5% EtOAc in pet ether; Rf: 0.8.

References: [1]Patent: US2015/166505,2015,A1 .Location in patent: Paragraph 0426; 0427.
[2]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00356.

13
[ 141-52-6 ]
[ 823221-93-8 ]
5-bromo-2-ethoxy-4-(trifluoromethyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	In ethanol; for 2h;Reflux;	To a solution of <strong>[823221-93-8]5-bromo-2-chloro-4-trifluoromethyl-pyridine</strong> (1.0 g, 3.84 mmol) in EtOH (5 mL) was added freshly prepared 1M solution of sodium ethanolate in EtOH (5.76 mL, 5.76 mmol) at RT and the resulting RM was heated to reflux for 2 h. The RM was concentrated under reduced pressure and subsequently diluted with CH2Cl2, washed with water and brine and dried. The solvent was evaporated under reduced pressure to yield the desired compound (700 mg, 67%) which was used in next step without further purification.

References: [1]Patent: US2015/166505,2015,A1 .Location in patent: Paragraph 0393; 0394.

14
[ 823221-93-8 ]
N-(3,5-difluoro-pyridin-4-yl)-5-[6-ethoxy-4-(trifluoromethyl)-pyridin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic acid amide [ No CAS ]

References: [1]Patent: US2015/166505,2015,A1 .

15
[ 823221-93-8 ]
N-(2,6-difluoro-phenyl)-5-[6-ethoxy-4-(trifluoromethyl)-pyridin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic acid amide [ No CAS ]

References: [1]Patent: US2015/166505,2015,A1 .

16
[ 823221-93-8 ]
C₁₄H₁₄F₃N₃O₃ [ No CAS ]

References: [1]Patent: US2015/166505,2015,A1 .

17
[ 823221-93-8 ]
C₁₃H₁₂F₃N₃O₃ [ No CAS ]

References: [1]Patent: US2015/166505,2015,A1 .

18
[ 823221-93-8 ]
C₁₂H₁₀F₃N₃O₃ [ No CAS ]

References: [1]Patent: US2015/166505,2015,A1 .

19
[ 823221-93-8 ]
C₁₃H₉F₆N₃O₅S [ No CAS ]

References: [1]Patent: US2015/166505,2015,A1 .

20
[ 823221-93-8 ]
C₁₅H₁₄F₃N₃O₂ [ No CAS ]

References: [1]Patent: US2015/166505,2015,A1 .

21
(1S,1aS,6aR)-4-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyloxy]-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid ethyl ester [ No CAS ]
[ 823221-93-8 ]
(1S,1aS,6aR)-4-((5-(6-chloro-4-(trifluoromethyl)pyridin-3-yl)-2-fluorobenzyl)oxy)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,2-dimethoxyethane; at 90℃;Inert atmosphere;	Step C. (1 S, 1 aS,6aR)-4-((5-(6-chloro-4-(trifluoromethyl)pyridin-3-yl)-2-fluorobenzyl)oxy)- l, la,6,6a-tetrahvdrocyclopropara1indene-l -carboxylic acid, ethyl ester 5-Bromo-2-chloro-4-(trifluoromethyl)pyridine (974 mg, 3.74 mmol) was added to a solution of (l S,laS,6aR)-4-((2-fluoro-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2- yl)benzyl)oxy)-l, la,6,6a-tetrahydrocyclopropa[a]indene-l -carboxylic acid, ethyl ester (1.583 g, 3.5 mmol) in DME (20 ml) under N2, followed by potassium carbonate (2.43 g, 17.58 mmol) and l,l'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (35 mg, 0.043 mmol). The mixture was heated at 90C overnight. It was poured into saturated NH4CI solution and extracted with EtOAc (lx). The organic phase was washed with brine, dried (MgS04), filtered and the solvent evaporated. The residue was purified on silica gel using hexane and to give the title compound. MS m/e: (M+H)+ 506, 508.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,2-dimethoxyethane; at 90℃;Inert atmosphere;	Step C. (1 S, 1 aS,6aR)-4-((5-(6-chloro-4-(trifluoromethyl)pyridin-3-yl)-2-fluorobenzyl)oxy)- l, la,6,6a-tetrahvdrocyclopropara1indene-l -carboxylic acid, ethyl ester 5-Bromo-2-chloro-4-(trifluoromethyl)pyridine (974 mg, 3.74 mmol) was added to a solution of (l S,laS,6aR)-4-((2-fluoro-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2- yl)benzyl)oxy)-l, la,6,6a-tetrahydrocyclopropa[a]indene-l -carboxylic acid, ethyl ester (1.583 g, 3.5 mmol) in DME (20 ml) under N2, followed by potassium carbonate (2.43 g, 17.58 mmol) and l,l'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (35 mg, 0.043 mmol). The mixture was heated at 90C overnight. It was poured into saturated NH4CI solution and extracted with EtOAc (lx). The organic phase was washed with brine, dried (MgS04), filtered and the solvent evaporated. The residue was purified on silica gel using hexane and to give the title compound. MS m/e: (M+H)+ 506, 508.

References: [1]Patent: WO2015/89809,2015,A1 .Location in patent: Page/Page column 96.
[2]Patent: WO2015/95256,2015,A1 .Location in patent: Page/Page column 97.

22
[ 680-15-9 ]
[ 401892-47-5 ]
[ 823221-93-8 ]

Yield	Reaction Conditions	Operation in experiment
64%	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 6h;	To a stirred solution of 5-bromo-2-chloro-4-iodopyridine (40 g, 126.2 mmol, 1 eq) in DMF (400 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (32.1 mL, 252.5 mmol, 2 eq) followed by CuT (48.2 g, 252.5 mmol, 2 eq). The resulting mixture was heated at 100 C for 6 h. TLC analysis indicated formation of a non-polar spot. The reaction mixture was diluted with water (200 mL), filtered through a celite pad and washed with n-pentane (2 x 500 mL) and followed by cold water (3 x 1000 mL). Organic layers were separated, dried over Na2SO4 and concentrated under reduced pressure at 30 C resulted 5-bromo-2-chloro-4-(trifluoromethyl)pyridine (21 g, 64% yield) as a liquid compound. TLC: 5% EtOAc in pet ether; Rf: 0.7
55.2%	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 6h;Inert atmosphere;	To a stirred solution of 5-bromo-2-chloro-4-iodopyridine (20.0 g, 63.09 mmol, 1.0 eq) in DMF (200 mL), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (16.15 mL, 126.18 mmol, 2.0 eq) and Cul (24.02 g, 126.18 mmol, 2.0 eq) were added at RT under argon atmosphere and the reaction mixture was heated to 100C for 6h. TLC analysis indicated a non-polar spot. The reaction mixture was diluted with water (200 mL) and filtered off and washed with w-pentane (1L) and cold water (3L). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure at 30C. The crude compound was purified by column chromatography (Silica gel, 100-200 mesh) using 5% EtOAc in pet ether as an eluent to afford the title compound (9.0 g, 55.2%) as a liquid compound. TLC: 5% EtOAc in pet ether; Rf: 0.7
44%	With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 6h;Inert atmosphere;	To a stirred solution of 5-bromo-2-chloro-4-iodopyridine (20.0 g, 63.09 mmol) in DMF (200 mL), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (16.15 mL, 126.18 mmol) and Cul (24.02 g, 126.18 mmol) were added at RT under argon atmosphere. The reaction mixture was heated to 100 C for 6 hours. The reaction mixture was diluted with water (200 mL) filtered off and washed with w-pentane (2 X 500 mL) and cold water (3 X 1000 mL). The separated organic layer dried over with sodium sulfate and concentrated under reduced pressure at 30 C to give the crude compound. That was purified by column chromatography (5% pet ether: EtO Ac) that resulted in the title compound (9.0g, 44%) as a liquid compound. TLC: 5% EtO Ac in pet ether. LCMS [M+H]+ = 261.0 g/mol.

References: [1]Patent: WO2019/46944,2019,A1 .Location in patent: Paragraph 00162.
[2]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00355.
[3]Patent: WO2017/147701,2017,A1 .Location in patent: Paragraph 00320; 00322-00323.

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[ 823221-93-8 ]
N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide [ No CAS ]