[ CAS No. 1211580-54-9 ] {[proInfo.proName]}

Name: 1211580-54-9|4-Bromo-2-(difluoromethyl)pyridine|95%
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SKU: A199625
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Quality Control of [ 1211580-54-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 1211580-54-9 ]

CAS No. :	1211580-54-9	MDL No. :	MFCD18257229
Formula :	C₆H₄BrF₂N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MNMLGZMORMDPJI-UHFFFAOYSA-N
M.W :	208.00	Pubchem ID :	58579539
Synonyms :

Calculated chemistry of [ 1211580-54-9 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	37.0
TPSA :	12.89 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.01 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.65
Log Po/w (XLOGP3) :	2.2
Log Po/w (WLOGP) :	3.3
Log Po/w (MLOGP) :	2.18
Log Po/w (SILICOS-IT) :	2.9
Consensus Log Po/w :	2.44

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.89
Solubility :	0.266 mg/ml ; 0.00128 mol/l
Class :	Soluble
Log S (Ali) :	-2.1
Solubility :	1.63 mg/ml ; 0.00786 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.49
Solubility :	0.0673 mg/ml ; 0.000324 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.59

Safety of [ 1211580-54-9 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P501-P260-P270-P264-P280-P303+P361+P353-P301+P330+P331-P363-P301+P312+P330-P304+P340+P310-P305+P351+P338+P310-P405	UN#:	1759
Hazard Statements:	H302-H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 1211580-54-9 ]

* 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 [ 1211580-54-9 ]
Downstream synthetic route of [ 1211580-54-9 ]

[ 1211580-54-9 ] Synthesis Path-Upstream 1~1

1
[ 131747-63-2 ]
[ 1211580-54-9 ]

Yield	Reaction Conditions	Operation in experiment
54%	at 20℃; for 16 h;	[0207] Step 1: 4-Bromo-2-(difluoromethyl)pyridine : To a 4- bromopicolinaldehyde (5.0 g, 26.88 mmol) was added diethylaminosulfur trifluoride (7.03 mL, 53.7 mmol), and the mixture was stirred at rt for 16 h. The reaction was quenched with aq. sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with brine (2 X 50 mL), dried over sodium sulfate, filtered, concentrated and purified by column chromatography (100- 200 silica) using 5percent ethyl acetate in hexane as eluent to afford 4-bromo-2- (difluoromethyl)pyridine (3.0 g, 14.492 mmol, 54percent yield ). ^lH NMR (400 MHz, CDC1₃) δ = 8.48 (d, J = 4.9 Hz, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.66-7.50 (m, 1H), 6.60 (t, 1H). LCMS: 207.9 [M+H]⁺.
49.7%	With diethylamino-sulfur trifluoride In chloroform at 0 - 20℃; for 12 h;	DAST (0.620 mL, 4.69 mmol) was added dropwise to a solution of 4-bromopicolinaldehyde (700 mg, 3.76 mmol) in Chloroform (21 mL) at 0° C. The reaction mixture was stirred at 20° C. for 12 h. The reaction mixture was poured in to saturated NaHCO₃solution (20 mL), and was extracted with DCM (2×20 mL). The DCM layer was dried over anhydrous Na₂SO₄, filtered and filtrate was evaporated to afford 4-bromo-2-(difluoromethyl)pyridine (400 mg, 1.870 mmol, 49.7percent yield) as light yellow solid, LCMS (m/z) 208.0 [M+H]⁺.
49.7%	With N,N-diethyltrifluoromethanesulfenamide In chloroform at 0 - 20℃; for 12 h;	DAST (0.620 mL, 4.69 mmol) was added dropwise to a solution of 4- bromopicolinaldehyde (700 mg, 3.76 mmol) in Chloroform (21 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 12h. The reaction mixture was poured in to saturated NaHC03 solution (20 mL), and was extracted with DCM (IX 20 mL). The DCM layer was dried over anhydrous Na2S04, filtered and filtrate was evaporated to afford 4-bromo- 2-(difluoromethyl)pyridine (400 mg, 1.870 mmol, 49.7 percent yield) as light yellow solid, LCMS (m/z) 208.0 [M+H]+.

32%	With diethylamino-sulfur trifluoride In chloroform at 0 - 20℃; Inert atmosphere	Example 30i 4-Bromo-2-(difluoromethyl)pyridine Diethylaminosulphur trifluoride (4.08 mL, 33.31 mmol) was added to 4-bromopicolinaldehyde (0.267 M in chloroform) (100 mL, 26.7 mmol) at 0° C. under an atmosphere of argon. The reaction mixture was stirred over night while the temperature was raised to room temperature. The reaction was quenched by addition of aqueous sodium bicarbonate (sat.) and was further diluted with dichloromethane. The solids were filtered off through a pad of Celite.(R).. The organic layer was collected and the water phase was extracted with dichloromethane (*3). The organic layers were pooled, dried (Na₂SO₄), filtered and concentrated. Purification by silica chromatography using 0 to 60percent diethyl ether in pentane gave the title compound (1.78 g, 32percent). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.59 (d, 1H) 7.98 (d, 1H) 7.90 (dt, 1H) 6.98 (t, 1 H); MS (APCI+) m/z 208, 210 [M+H]⁺.
800 mg	With diethylamino-sulfur trifluoride In dichloromethane at 0 - 20℃; Inert atmosphere	Description 1284-Bromo-2-(difluoromethyl)pyridine (D128)To a solution of 4-bromopicolinaldehyde (1 g) in DCM (20 mL) stirred under nitrogen atmosphere at 0°C was added DAST (1.065 mL). The reaction mixture was stirred at RT overnight. To the mixture was added water, and then extracted with DCM (3 x50 mL). The organic phase was washed with saturated NaHCO3, water, and brine, then dried over MgSO4 and filtered to give the titlecompound (800 mg) as yellow oil. MS (ESI): C6H4BrF2N requires 207; found no mass.

Reference： [1] Patent: WO2016/161160, 2016, A1, . Location in patent: Paragraph 0207
[2] Patent: US2015/152108, 2015, A1, . Location in patent: Paragraph 0480; 0481
[3] Patent: WO2016/79709, 2016, A1, . Location in patent: Page/Page column 179
[4] Patent: US2010/125082, 2010, A1, . Location in patent: Page/Page column 24; 25
[5] Patent: WO2015/180612, 2015, A1, . Location in patent: Page/Page column 78

[ 1211580-54-9 ] Synthesis Path-Downstream 1~33

1
[ 131747-63-2 ]
[ 1211580-54-9 ]

Yield	Reaction Conditions	Operation in experiment
54%	With diethylamino-sulfur trifluoride; at 20℃; for 16h;	[0207] Step 1: 4-Bromo-2-(difluoromethyl)pyridine : To a 4- bromopicolinaldehyde (5.0 g, 26.88 mmol) was added diethylaminosulfur trifluoride (7.03 mL, 53.7 mmol), and the mixture was stirred at rt for 16 h. The reaction was quenched with aq. sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with brine (2 X 50 mL), dried over sodium sulfate, filtered, concentrated and purified by column chromatography (100- 200 silica) using 5% ethyl acetate in hexane as eluent to afford 4-bromo-2- (difluoromethyl)pyridine (3.0 g, 14.492 mmol, 54% yield ). lH NMR (400 MHz, CDC13) delta = 8.48 (d, J = 4.9 Hz, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.66-7.50 (m, 1H), 6.60 (t, 1H). LCMS: 207.9 [M+H]+.
49.7%	With diethylamino-sulfur trifluoride; In chloroform; at 0 - 20℃; for 12h;	DAST (0.620 mL, 4.69 mmol) was added dropwise to a solution of <strong>[131747-63-2]4-bromopicolinaldehyde</strong> (700 mg, 3.76 mmol) in Chloroform (21 mL) at 0 C. The reaction mixture was stirred at 20 C. for 12 h. The reaction mixture was poured in to saturated NaHCO3 solution (20 mL), and was extracted with DCM (2×20 mL). The DCM layer was dried over anhydrous Na2SO4, filtered and filtrate was evaporated to afford 4-bromo-2-(difluoromethyl)pyridine (400 mg, 1.870 mmol, 49.7% yield) as light yellow solid, LCMS (m/z) 208.0 [M+H]+.
49.7%	With N,N-diethyltrifluoromethanesulfenamide; In chloroform; at 0 - 20℃; for 12h;	DAST (0.620 mL, 4.69 mmol) was added dropwise to a solution of 4- bromopicolinaldehyde (700 mg, 3.76 mmol) in Chloroform (21 mL) at 0 C. The reaction mixture was stirred at 20 C for 12h. The reaction mixture was poured in to saturated NaHC03 solution (20 mL), and was extracted with DCM (IX 20 mL). The DCM layer was dried over anhydrous Na2S04, filtered and filtrate was evaporated to afford 4-bromo- 2-(difluoromethyl)pyridine (400 mg, 1.870 mmol, 49.7 % yield) as light yellow solid, LCMS (m/z) 208.0 [M+H]+.

32%	With diethylamino-sulfur trifluoride; In chloroform; at 0 - 20℃;Inert atmosphere;	Example 30i 4-Bromo-2-(difluoromethyl)pyridine Diethylaminosulphur trifluoride (4.08 mL, 33.31 mmol) was added to <strong>[131747-63-2]4-bromopicolinaldehyde</strong> (0.267 M in chloroform) (100 mL, 26.7 mmol) at 0 C. under an atmosphere of argon. The reaction mixture was stirred over night while the temperature was raised to room temperature. The reaction was quenched by addition of aqueous sodium bicarbonate (sat.) and was further diluted with dichloromethane. The solids were filtered off through a pad of Celite. The organic layer was collected and the water phase was extracted with dichloromethane (*3). The organic layers were pooled, dried (Na2SO4), filtered and concentrated. Purification by silica chromatography using 0 to 60% diethyl ether in pentane gave the title compound (1.78 g, 32%). 1H NMR (400 MHz, DMSO-d6) delta ppm 8.59 (d, 1H) 7.98 (d, 1H) 7.90 (dt, 1H) 6.98 (t, 1 H); MS (APCI+) m/z 208, 210 [M+H]+.
32%	With diethylamino-sulfur trifluoride; In chloroform; at 0 - 20℃;Inert atmosphere;	To a solution of <strong>[131747-63-2]4-bromopicolinaldehyde</strong> (10 g, 53.76 mmol) in CHCI3 (200.0 mL) was added diethylaminosulfur trifluoride (8.5 mL, 64.51 mmol) at 0C under argon. The reaction mixture was stirred overnight while the temperature was raised to room temperature. The reaction was quenched by addition of aqueous NaHC03 and further diluted with CH2CI2. The solids were filtered off through a pad of celite. The organic layer was separated and aqueous phase was extracted with CH2CI2 (3x). The organic phase dried over Na2S04. The suspension was concentrated to dryness and the resulting crude product was purified by Teledyne-Isco flash system by using Hexane/EtOAc, 0 to 20% of ethyl acetate in hexane to provide compound 16 as light yellow liquid (3.5 g, 32% yield). lH NMR (400 MHz, DMSO-d6) delta (ppm): 8.79 (d, 1H), 7.98 (s, 1H), 7.80 (d, 1H), 4.86 (s, 1H).
800 mg	With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃;Inert atmosphere;	Description 1284-Bromo-2-(difluoromethyl)pyridine (D128)To a solution of <strong>[131747-63-2]4-bromopicolinaldehyde</strong> (1 g) in DCM (20 mL) stirred under nitrogen atmosphere at 0C was added DAST (1.065 mL). The reaction mixture was stirred at RT overnight. To the mixture was added water, and then extracted with DCM (3 x50 mL). The organic phase was washed with saturated NaHCO3, water, and brine, then dried over MgSO4 and filtered to give the titlecompound (800 mg) as yellow oil. MS (ESI): C6H4BrF2N requires 207; found no mass.

Reference： [1]Patent: WO2016/161160,2016,A1 .Location in patent: Paragraph 0207
[2]Patent: US2015/152108,2015,A1 .Location in patent: Paragraph 0480; 0481
[3]Patent: WO2016/79709,2016,A1 .Location in patent: Page/Page column 179
[4]Patent: US2010/125082,2010,A1 .Location in patent: Page/Page column 24; 25
[5]Patent: WO2019/5297,2019,A1 .Location in patent: Page/Page column 33-34
[6]Patent: WO2015/180612,2015,A1 .Location in patent: Page/Page column 78

2
[ 1211580-54-9 ]
[ 1227162-95-9 ]
[ 1227163-02-1 ]

Yield	Reaction Conditions	Operation in experiment
18%		Example 31i 1-(3-Bromophenyl)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1H-isoindol-3-amine n-Butyllithium (0.254 mL, 0.63 mmol) was dropwise added to <strong>[1211580-54-9]4-bromo-2-(difluoromethyl)pyridine</strong> (120 mg, 0.58 mmol) in anhydrous THF (5.00 mL) at -78 C. under argon atmosphere. The reaction mixture was stirred for 25 min. N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (235 mg, 0.58 mmol) in anhydrous THF (5.00 mL) was dropwise added. The reaction mixture was stirred for 2 h, then methanol (5 mL) was added and the temperature was allowed to reach room temperature. The reaction mixture was partitioned between aqueous ammonium chloride and ethyl acetate. The aqueous phase was extracted with ethyl acetate (*3). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by prep. HPLC to afford the title compound (47.1 mg, 18%). 1H NMR (500 MHz, DMSO-d6) delta ppm 8.60 (d, 1H) 7.67 (d, 1H) 7.57 (td, 1H) 7.52-7.55 (m, 1H) 7.45-7.50 (m, 2H) 7.42-7.45 (m, 1H) 7.25-7.35 (m, 3H) 6.92 (t, 1H) 6.77 (br. s., 1H); MS (ES+) m/z 432, 434 [M+H]+.

Reference： [1]Patent: US2010/125082,2010,A1 .Location in patent: Page/Page column 25

3
[ 1211580-54-9 ]
[ 1227162-99-3 ]
[ 1227163-03-2 ]

Yield	Reaction Conditions	Operation in experiment
20%		Example 32i 1-(2-Bromopyridin-4-yl)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1H-isoindol-3-amine n-Butyllithium (2.5 M in hexane) (0.353 mL, 0.88 mmol) was added to <strong>[1211580-54-9]4-bromo-2-(difluoromethyl)pyridine</strong> (183 mg, 0.88 mmol) in THF (7 mL) at -78 C. under argon atmosphere. The reaction was stirred for 30 min before N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 0.73 mmol) in THF (2 mL) was added. The reaction was kept at -78 C. for 1 hour and then allowed to reach room temperature. Methanol (5 mL) was added followed by hydrochloric acid (1 M in diethylether) (2.204 mL, 2.20 mmol) and the reaction was stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between aqueous sodium bicarbonate (sat.) and ethyl acetate. The aqueous phase was extracted with EtOAc (*3). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by prep. HPLC to afford the title compound (64 mg, 20%). 1H NMR (400 MHz, DMSO-d6) delta ppm 8.62 (d, 1H) 8.33 (dd, 1H) 7.76 (d, 1H) 7.61 (td, 1H) 7.54 (s, 1H) 7.46-7.50 (m, 2H) 7.32-7.40 (m, 2H) 6.78-7.10 (m, 3H); MS (ES+) m/z 433, 435 [M+H]+.

Reference： [1]Patent: US2010/125082,2010,A1 .Location in patent: Page/Page column 25

4
[ 1211580-54-9 ]
[ 1571135-77-7 ]

Yield	Reaction Conditions	Operation in experiment
60%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; bis(pinacol)diborane; In 1,4-dioxane; at 80℃; for 48h;	A mixture of <strong>[1211580-54-9]4-bromo-2-(difluoromethyl)pyridine</strong> (2.50 g, 12.0 mmol), bis-(pinakolato)-diboron (3.80 g, 15.0 mmol), (1,1'-Bis-(diphenylphosphino)-ferrocen)-dichlorpalladium(II) (26 mg, 36 mumol) and potassium acetate (2.90 g, 30.0 mmol) in dioxane is stirred for 48 h at 80 C. The volatiles are removed under reduced pressure. After addition of water, the mixture is extracted with dichloromethane. The combined organic layer is dried over Na2SO4 and evaporated under reduced pressure. The remaining residue is purified by preparative reversed phase HPLC (Sunfire, gradient of acetonitrile in water, 0.1% HCOOH). Yield: 599 mg of the desired boronic acid (60% pure, 17% of theory).
57.6%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; bis(pinacol)diborane; In 1,4-dioxane; at 28 - 80℃; for 48h;Inert atmosphere;	Potassium acetate (472 mg, 4.81 mmol) was added to a stirred solution of <strong>[1211580-54-9]4-bromo-2-(difluoromethyl)pyridine</strong> (400 mg, 1.923 mmol), and bis(pinacolato)diboron (610 mg, 2.404 mmol) in 1,4-Dioxane (10 mL) at 28 C. The reaction mixture was degassed for 15 min, was added PdCl2(dppf) (4.22 mg, 5.77 mumol). The reaction mixture was further degassed for 15 min, and the reaction mixture was stirred for 48 hr at 80 C. The reaction mixture was cooled to 28 C., was evaporated and crude was partitioned between water (10 mL) and EtOAc (25 mL). EtOAc layer was separated and was dried over anhydrous Na2SO4, filtered, and filtrate was evaporated to afford (2-(difluoromethyl)pyridin-4-yl)boronic acid (330 mg, 1.107 mmol, 57.6% yield) as brown solid, LCMS (m/z) 174.1 [M+H]+.
57.6%	With (3-phenylallyl)(chloro)-[1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]palladium(II); potassium acetate; bis(pinacol)diborane; In 1,4-dioxane; at 28 - 80℃; for 48h;	Potassium acetate (472 mg, 4.81 mmol) was added to a stirred solution of 4-bromo-2- (difluoromethyl)pyridine (400 mg, 1.923 mmol), and bis(pinacolato)diboron (610 mg, 2.404 mmol) in 1,4-Dioxane (10 mL) at 28 C. The reaction mixture was degassed for 15 min, was added PdCl2(dppf) (4.22 mg, 5.77 muiotaetaomicron). The reaction mixture was further degassed for 15 min, and the reaction mixture was stirred for 48 hr at 80 C. The reaction mixture was cooled to 28 C, was evaporated and crude was partitioned between water (10 mL) and EtOAc (25 mL). EtOAc layer was separated and was dried over anhydrous Na2S04, filtered, and filtrate was evaporated to afford (2-(difluoromethyl)pyridin-4- yl)boronic acid (330 mg, 1.107 mmol, 57.6 % yield) as brown solid, LCMS (m/z) 174.1 [M+H]+.

A mixture of <strong>[1211580-54-9]4-bromo-2-(difluoromethyl)pyridine</strong> (2.50 g, 12.0 mmol), bis-(pinakolato)-diboron (3.80 g, 15.0 mmol), (l, -Bis-(diphenylphosphino)-ferrocen)-dichlorpalladium(II) (26 mg, 36 muiotaetaomicron) and potassium acetate (2.90 g, 30.0 mmol) in dioxane is stirred for 48 h at 80C. The volatiles are removed under reduced pressure. After addition of water, the mixture is extracted with dichloromethane. The combined organic layer is dried over Na2S04 and evaporated under reduced pressure. The remaining residue is purified by preparative reversed phase HPLC (Sunfire, gradient of acetonitrile in water, 0.1% HCOOH). Yield: 599 mg of the desired boronic acid (60% pure, 17% of theory).

Reference： [1]Patent: US2014/57916,2014,A1 .Location in patent: Paragraph 0490
[2]Patent: US2015/152108,2015,A1 .Location in patent: Paragraph 0482; 0483
[3]Patent: WO2016/79709,2016,A1 .Location in patent: Page/Page column 180
[4]Patent: WO2014/29831,2014,A1 .Location in patent: Page/Page column 136

5
[ 1211580-54-9 ]
(9S)-5-[2-(difluoromethyl)pyridin-4-yl]-N-(pyrazin-2-yl)-1,6,8-triazatricyclo[7.2.1.0^2,7]dodeca-2⁽⁷⁾,3,5-triene-8-carboxamide [ No CAS ]

Reference： [1]Patent: US2015/152108,2015,A1
[2]Patent: WO2016/79709,2016,A1

6
[ 1211580-54-9 ]
[ 1256818-14-0 ]

Reference： [1]Patent: WO2015/180612,2015,A1

7
[ 1211580-54-9 ]
[ 1225047-28-8 ]

Reference： [1]Patent: WO2015/180612,2015,A1

8
[ 67-56-1 ]
[ 201230-82-2 ]
[ 1211580-54-9 ]
[ 1251844-44-6 ]

Yield	Reaction Conditions	Operation in experiment
500 mg	With triethylamine; diphenyl(pyren-1-yl)phosphane; In N,N-dimethyl-formamide; at 120℃; under 12160.8 Torr; for 8h;Sealed tube;	Description 129Methyl 2-(difluoromethyl)isonicotinate (D129)F11:10To a mixture of <strong>[1211580-54-9]4-bromo-2-(difluoromethyl)pyridine</strong> (D128, 900 mg), DPPP (357 mg),triethylamine (0.603 mL) in methanol (20 mL) and DMF (5 mL) was passed CO gas for 3 mm. The mixture was then heated to 120C in a sealed vial at 16 atm for 8 hours. After cooling to RT, the mixture was concentrated. Water was added, extracted with EtOAc (3 x50 mL). The organic layer was washed with saturated NaHCO3 solution (10 mL), water (10 mL), and brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (silicagel, petroleum ether/EtOAc = 5:1) to afford the title compound (500 mg) as yellow oil. MS (ESI):C8H7F2N02 requires 187; found 188 [M+H].

Reference： [1]Patent: WO2015/180612,2015,A1 .Location in patent: Page/Page column 78

9
[ 1211580-54-9 ]
[ 1429747-38-5 ]
N-[2-(difluoromethyl)pyridin-4-yl]-2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-5-methoxypyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl-formamide; at 105℃;	ntermediate 1-3-1Preparation of N-[2-(difluoromethyl)pyridin-4-yl]-2-[1 -(4-ethoxy-2,6-difluorobenzyl)-1 H- indazol-3-yl]-5-methoxypyrimidin-4-amine100 mg of 2-[1 -(4-ethoxy-2,6-difluorobenzyl)-1 H-indazol-3-yl]-5-methoxypyrimidin-4- amine 1 -4-1 (0.24 mmol, 1 .0 eq.) was dissolved in 0.9 mL DMF. 56 mg of 4-bromo-2- (difluoromethyl)pyridine (0.27 mmol, 1 .1 eq.), 238 mg of cesium carbonate (0.73 mmol, 3.0 eq), 5.5 mg of palladium(ll)acetate (0.024 mmol, 0.1 eq.) and 21 mg of 4,5- Bis(diphenylphosphino)-9,9-dimethylxanthene (0.036 mmol, 0.15 eq.) were added and the mixture was stirred at 105 over night. The r eaction mixture was diluted with water and dichloromethane. The layers were seperated and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried using a waterresistant filter and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatografy and HPLC to provide the analytically pure target compound: 39 mg, 0.07 mmol, 30%.1H-NMR (400MHz, DMSO-de): delta [ppm]= 1.27 (t, 3H), 3.95 - 4.10 (m, 5H), 5.69 (s, 2H), 6.73 - 6.82 (m, 2H), 6.85 (t, 1 H), 7.19 - 7.29 (m, 1 H), 7.44 - 7.53 (m, 1 H), 7.81 (d, 1 H), 8.35 (d, 1 H), 8.39 (s, 1 H), 8.45 (d, 1 H), 8.47 - 8.56 (m, 2H), 9.69 (s, 1 H).

Reference： [1]Patent: WO2016/42080,2016,A1 .Location in patent: Page/Page column 129; 130

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[ 1211580-54-9 ]
3-[(4-{bis[2-(difluoromethyl)pyridin-4-yl]amino}-2-[1-(4-ethoxy-2,6-di-fluorobenzyl)-1H-indazol-3-yl]pyrimidin-5-yl)oxy]propan-1-ol [ No CAS ]