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[ CAS No. 256417-10-4 ] {[proInfo.proName]}

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Chemical Structure| 256417-10-4

Chemical Structure| 256417-10-4

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Quality Control of [ 256417-10-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 256417-10-4 ]

Product Details of [ 256417-10-4 ]

CAS No. :	256417-10-4	MDL No. :	MFCD04114368
Formula :	C₈H₆F₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZYABCGOTMDPUDD-UHFFFAOYSA-N
M.W :	172.13	Pubchem ID :	3703713
Synonyms :

Calculated chemistry of [ 256417-10-4 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	38.24
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.24 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.62
Log Po/w (XLOGP3) :	1.56
Log Po/w (WLOGP) :	2.63
Log Po/w (MLOGP) :	1.97
Log Po/w (SILICOS-IT) :	2.82
Consensus Log Po/w :	2.12

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.13
Solubility :	1.28 mg/ml ; 0.00745 mol/l
Class :	Soluble
Log S (Ali) :	-1.72
Solubility :	3.26 mg/ml ; 0.019 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.03
Solubility :	0.162 mg/ml ; 0.00094 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.29

Safety of [ 256417-10-4 ]

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

Application In Synthesis of [ 256417-10-4 ]

* 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 [ 256417-10-4 ]
Downstream synthetic route of [ 256417-10-4 ]

[ 256417-10-4 ] Synthesis Path-Upstream 1~5

1
[ 617-84-5 ]
[ 372-18-9 ]
[ 93343-10-3 ]
[ 256417-10-4 ]
[ 437-81-0 ]

Reference： [1] Chemistry - A European Journal, 2017, vol. 23, # 43, p. 10280 - 10284

2
[ 4885-02-3 ]
[ 93343-10-3 ]
[ 608515-57-7 ]
[ 256417-10-4 ]

Yield	Reaction Conditions	Operation in experiment
19%	at 0℃; for 1 h;	(Intermediates 26A and 26B were prepared in a similar manner to the preparation described in WO 2004046133). To a stirred solution of 3,5- difluoroanisole (l.Og, 7.0 mmol) in dichloromethane (6 mL) at 0 0C was added dropwise titanium tetrachloride (1.23 mL, 11.2 mmol) and dichloromethyl methyl ether (0.63 mL, 7.0 mmol). Upon completion of addition, the reaction mixture was stirred for Ih and then poured into ice-water (50 mL). The resulting mixture was extracted with dichloromethane (3x 50 mL). The combined organics were washed with H2O (50 mL), brine (50 mL), dried over Na2SO4 and filtered. The volatiles were removed under reduced pressure to provide a residue. The residue was subjected to chromatography on silica gel eluting with 0 to 20percent EtOAc/hexanes to give 2,6- difluoro-4-methoxybenzaldehyde, Intermediate 26 A [less polar material, 230 mg, 19percent, 1H NMR (400 MHz, CDCl3) ? ppm 3.85 (s, 3 H), 6.47 (d, J=10.55 Hz, 2 H), 10.17 (s, 1 H)] and 2,4-difluoro-6-methoxybenzaldehyde, Intermediate 26B [more polar material, 740 mg, 62percent, 1H NMR (400 MHz, CDCl3) ? ppm 3.91 (s, 3 H) 6.43 - 6.51 (m, 2 H) 10.30 (s, 1 H)], both as white solids.

Reference： [1] Patent: WO2007/30582, 2007, A2, . Location in patent: Page/Page column 90

3
[ 68-12-2 ]
[ 256417-10-4 ]

Reference： [1] Patent: WO2007/149448, 2007, A2, . Location in patent: Page/Page column 68-69

4
[ 331-64-6 ]
[ 256417-10-4 ]

Reference： [1] Journal of the American Chemical Society, 2018, vol. 140, # 8, p. 2789 - 2792

5
[ 617-84-5 ]
[ 372-18-9 ]
[ 93343-10-3 ]
[ 256417-10-4 ]
[ 437-81-0 ]

Reference： [1] Chemistry - A European Journal, 2017, vol. 23, # 43, p. 10280 - 10284

[ 256417-10-4 ] Synthesis Path-Downstream 1~88

1
[ 68-12-2 ]
[ 256417-10-4 ]

Yield	Reaction Conditions	Operation in experiment
		3,5-Difluoroanisole (5 g, 34.7 mmol) was dissolved in tetrahydrofuran (73 mL) and cooled to -78 0C. A solution of «-butyl lithium (2.5 M solution in tetrahydrofuran, 2.5 mL, 2.50 mmol ) was slowly added, and the reaction mixture was stirred at -78 0C for 1.5 h. At this point, N,iV-dimethylformamide (10 mL) was added, and the reaction was stirred for 10 minutes at -78 C and then another 10 minutes at 0 0C. The reaction mixture was then quenched with 50 mL of IM HCl. The reaction mixture was extracted with ethyl acetate (3 <n="70"/>x 50 mL)5 the organic layers combined, dried over MgSC>4, concentrated and the crude oil was purified by MPLC (0 to 20 % gradient of ethyl acetate in hexanes as eluant) to yield 5.45 g of the title product as a fluffy yellow solid. 1H NMR (CDCl3) 5 10.20 (s, IH), 6.49 (d, 2H), 3.87 (s, 3H).

Reference： [1]Patent: WO2007/149448,2007,A2 .Location in patent: Page/Page column 68-69

2
[ 256417-10-4 ]
[ 858114-78-0 ]

Yield	Reaction Conditions	Operation in experiment
52%		Reference Example 26 ethyl (2E)-3-(2,6-difluoro-4-methoxyphenyl)acrylate A solution of ethyl diethylphosphonoacetate (2.34 g, 10.4 mmol) and 60% sodium hydride (0.38 g, 9.50 mmol) in tetrahydrofuran (40 mL) was stirred under ice-cooling for 10 min. Thereto was added <strong>[256417-10-4]2,6-difluoro-4-methoxybenzaldehyde</strong> (1.5 g, 8.71 mmol) and the mixture was stirred for 4 hr while allowing to warm to room temperature. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:10-1:5) to give the title compound (1.1 g, yield 52%) as colorless needles. MS: m/z 243 (M+H).
52%		A solution of ethyl diethylphosphonoacetate (2.34 g, 10.4 mmol) and sodium hydride (60% in oil, 0.38 g, 9.50 mmol) in tetrahydrofuran (40 mL) was stirred under ice-cooling for 10 min. <strong>[256417-10-4]2,6-Difluoro-4-methoxybenzaldehyde</strong> (1.5 g, 8.71 mmol) was added to the solution, and the mixture was stirred for 4 hr while raising the temperature to room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:10-1:5) to give the title compound (1.1 g, yield 52%) as colorless needle crystals. MS: m/z 243 (MH+).

Reference： [1]Patent: EP1698624,2006,A1 .Location in patent: Page/Page column 40
[2]Patent: EP1731505,2006,A1 .Location in patent: Page/Page column 33

4
[ 4885-02-3 ]
[ 93343-10-3 ]
[ 608515-57-7 ]
[ 256417-10-4 ]

Yield	Reaction Conditions	Operation in experiment
62%; 19%	titanium tetrachloride; In dichloromethane; at 0℃; for 1h;	(Intermediates 26A and 26B were prepared in a similar manner to the preparation described in WO 2004046133). To a stirred solution of 3,5- difluoroanisole (l.Og, 7.0 mmol) in dichloromethane (6 mL) at 0 0C was added dropwise titanium tetrachloride (1.23 mL, 11.2 mmol) and dichloromethyl methyl ether (0.63 mL, 7.0 mmol). Upon completion of addition, the reaction mixture was stirred for Ih and then poured into ice-water (50 mL). The resulting mixture was extracted with dichloromethane (3x 50 mL). The combined organics were washed with H2O (50 mL), brine (50 mL), dried over Na2SO4 and filtered. The volatiles were removed under reduced pressure to provide a residue. The residue was subjected to chromatography on silica gel eluting with 0 to 20% EtOAc/hexanes to give 2,6- difluoro-4-methoxybenzaldehyde, Intermediate 26 A [less polar material, 230 mg, 19%, 1H NMR (400 MHz, CDCl3) ? ppm 3.85 (s, 3 H), 6.47 (d, J=10.55 Hz, 2 H), 10.17 (s, 1 H)] and 2,4-difluoro-6-methoxybenzaldehyde, Intermediate 26B [more polar material, 740 mg, 62%, 1H NMR (400 MHz, CDCl3) ? ppm 3.91 (s, 3 H) 6.43 - 6.51 (m, 2 H) 10.30 (s, 1 H)], both as white solids.

Reference： [1]Patent: WO2007/30582,2007,A2 .Location in patent: Page/Page column 90

5
[ 867-13-0 ]
[ 256417-10-4 ]
C₁₂H₁₂F₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of ethyl diethylphosphonoacetate (2.34 g, 10.4 mml) and 60% sodium hydride (0.38 g, 9.50 mmol) in tetrahydrofuran (40 ml) was stirred under ice-cooling for 10 min. <strong>[256417-10-4]2,6-Difluoro-4-methoxybenzaldehyde</strong> (1.5 g, 8.71 mmol) was added, and the mixture was stirred while elevating the temperature to room temperature for 4 hrs. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (ethyl acetate:hexane=1:10-1:5), and then subjected to catalytic reduction in the same manner as in Reference Example 172 to give the title compound (1.17 g) as a colorless oil. yield 52%. MS 245.0 (MH+).

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1365 - 1378
[2]Patent: EP1559422,2005,A1 .Location in patent: Page/Page column 131

6
potassium cyanide [ No CAS ]
[ 372-19-0 ]
[ 256417-10-4 ]
[ 1193511-86-2 ]

Yield	Reaction Conditions	Operation in experiment
	With indium(III) chloride; In tetrahydrofuran; at 20℃;	Preparation of 2,6-alpha-[(3-fluorophenyl)amino)]-4-methoxybenzeneacetonitrile A mixture of 3-fluoroaniline (1.15 g, 10.4 mmol), 2,6-difluoro-4- methoxybenzaldehyde (2.00 g, 11.6 mmol), potassium cyanide (2.70 g, 41.6 mmol) and indium chloride (2.30 g, 10.4 mmol) in tetrahydrofuran (40 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (about 100 mL) and extracted with ethyl acetate. The combined ethyl acetate extracts were concentrated under reduced pressure to provide the title compound as an oil, which was carried directly on to Step B.
	With indium(III) chloride; In tetrahydrofuran; at 20℃;	Step A: Preparation of 2,6-alpha-[(3-fluorophenyl)amino)]-4-methoxybenzeneacetonitrileA mixture of 3-fluoroaniline (1.15 g, 10.4 mmol), <strong>[256417-10-4]2,6-difluoro-4-methoxybenzaldehyde</strong> (2.00 g, 11.6 mmol), potassium cyanide (2.70 g, 41.6 mmol) and indium chloride (2.30 g, 10.4 mmol) in tetrahydrofuran (40 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (about 100 mL) and extracted with ethyl acetate. The combined ethyl acetate extracts were concentrated under reduced pressure to provide the title compound as an oil, which was carried directly on to Step B.
	With indium chloride; In tetrahydrofuran; at 20℃;	4-methoxybenzaldehyde (2.00 g, 11.6 mmol), potassium cyanide (2.70 g, 41.6 mmol) and indium chloride (2.30 g, 10.4 mmol) in tetrahydrofuran (40 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (about 100 mL) and extracted with ethyl acetate. The combined ethyl acetate extracts were concentrated under reduced pressure to provide the title compound as an oil, which was carried directly on to Step B.

Reference： [1]Patent: WO2009/137538,2009,A2 .Location in patent: Page/Page column 62
[2]Patent: US2011/45101,2011,A1 .Location in patent: Page/Page column 32
[3]Patent: WO2011/56463,2011,A2 .Location in patent: Page/Page column 55

7
[ 256417-10-4 ]
[ 10272-07-8 ]
[ 1297597-81-9 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene;Reflux;	Preparation of lambda/-[(2,6-difluoro-4-methoxyphenyl)methylene]-3,5- dimethoxybenzenamine A mixture of 3,5-dimethoxybenzamine (2.00 g, 13.1 mmol) and 2,6-difluoro-4- methoxybenzaldehyde (2.30 g, 13.1 mmol) in toluene (40 mL) was heated at reflux overnight with use of a Dean-Stark trap for azeotropic removal of water. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to provide the title compound as a solid (4.00 g). 1H NMR (CDCl3): delta 8.56 (s, IH), 6.53 (m, 2H), 6.36 (m, 3H), 3.85 (s, 3H), 3.81 (s, 6H).
	In toluene; for 16h;Reflux;	Step A: Preparation of N-[(2,6-difluoro-4-methoxyphenyl)methylene]-3,5-dimethoxybenzenamineA mixture of 3,5-dimethoxybenzamine (2.00 g, 13.1 mmol) and <strong>[256417-10-4]2,6-difluoro-4-methoxybenzaldehyde</strong> (2.30 g, 13.1 mmol) in toluene (40 mL) was heated at reflux overnight with use of a Dean-Stark trap for azeotropic removal of water. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to provide the title compound as a solid (4.00 g).1H NMR (CDCl3): delta 8.56 (s, 1H), 6.53 (m, 2H), 6.36 (m, 3H), 3.85 (s, 3H), 3.81 (s, 6H).
	In toluene;Reflux; Dean-Stark trap;	A mixture of 3,5-dimethoxybenzamine (2.00 g, 13.1 mmol) and 2,6-difluoro- 4-methoxybenzaldehyde (2.30 g, 13.1 mmol) in toluene (40 mL) was heated at reflux overnight with use of a Dean-Stark trap for azeotropic removal of water. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to provide the title compound as a solid (4.00 g)..H NMR (CDCI3) delta 8.56 (s, 1H), 6.53 (m, 2H), 6.36 (m, 3H), 3.85 (s, 3H), 3.81 (s, 6H)

Reference： [1]Patent: WO2009/137538,2009,A2 .Location in patent: Page/Page column 61
[2]Patent: US2011/45101,2011,A1 .Location in patent: Page/Page column 32
[3]Patent: WO2011/56463,2011,A2 .Location in patent: Page/Page column 54

8
[ 256417-10-4 ]
[ 23100-12-1 ]
[ 1193511-89-5 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; for 16h;Reflux;	To a mixture of 2,6-difluoro-4-methoxybenzenamine (0.98 g, 6.9 mmol) in toluene(2O mL) was added 6-chloro-3-pyridinecarboxaldehyde (1.0 g, 6.3 mmol). The reaction mixture was heated at reflux with the use of a Dean-Stark trap for azeotropic removal of water. After 16 h the reaction mixture was cooled to room temperature and concentrated <n="76"/>under reduced pressure. The resulting material was dried in a vacuum oven at 55 0C overnight to provide the title compound as a light brown solid (1.66 g).1H NMR (CDCl3): delta 8.74 (s, IH), 8.73 (d, J = 2.44 Hz, IH), 8.32 (dd, J = 2.20 Hz, J =8.29 Hz, IH), 7.44 (d, J= 8.29 Hz, IH), 6.59-6.52 (m, 2H), 3.82 (s, 3H). 1F NMR (CDCl3): delta-121.48 to 121.40 (m, 2F).

Reference： [1]Patent: WO2009/137538,2009,A2 .Location in patent: Page/Page column 74-75

9
[ 256417-10-4 ]
[ 106877-33-2 ]
[ 1193511-88-4 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; for 60h;Reflux;	A mixture of 6-(trifluoromethyl)-3 -pyridinamine (5.00 g, 30.8 mmol) and <strong>[256417-10-4]2,6-difluoro-4-methoxybenzaldehyde</strong> (5.30 g, 30.8 mmol) in toluene (100 mL) was heated to reflux for2.5 days. Then the reaction mixture was concentrated under reduced pressure to provide the title compound as a solid (9.9 g). 1H NMR (CDCl3): delta 8.56 (s, IH), 8.52 (d, IH), 7.71 (d, IH), 7.60 (m, IH), 6.57 (m, 2H),3.88 (s, 3H).
	In toluene; for 60h;Reflux;	Step A: Preparation of N-[(2,6-difluoro-4-methoxyphenyl)methylene]-6-(trifluoromethyl)-3-pyridinamineA mixture of 6-(trifluoromethyl)-3-pyridinamine (5.00 g, 30.8 mmol) and <strong>[256417-10-4]2,6-difluoro-4-methoxybenzaldehyde</strong> (5.30 g, 30.8 mmol) in toluene (100 mL) was heated to reflux for 2.5 days. Then the reaction mixture was concentrated under reduced pressure to provide the title compound as a solid (9.9 g).1H NMR (CDCl3): delta 8.56 (s, 1H), 8.52 (d, 1H), 7.71 (d, 1H), 7.60 (m, 1H), 6.57 (m, 2H), 3.88 (s, 3H).
	In toluene; for 60h;Reflux;	A mixture of 6-(trifluoromethyl)-3-pyridinamine (5.00 g, 30.8 mmol) and 2,6-difluoro- 4-methoxybenzaldehyde (5.30 g, 30.8 mmol) in toluene (100 mL) was heated to reflux for 2.5 days. The reaction mixture was then concentrated under reduced pressure to provide the title compound as a solid (9.9 g).in NMR (CDC13) delta 8.56 (s, 1H), 8.52 (d, 1H), 7.71 (d, 1H), 7.60 (m, 1H), 6.57 (m, 2H), 3.88 (s, 3H).

Reference： [1]Patent: WO2009/137538,2009,A2 .Location in patent: Page/Page column 73
[2]Patent: US2011/45101,2011,A1 .Location in patent: Page/Page column 37
[3]Patent: WO2011/56463,2011,A2 .Location in patent: Page/Page column 63

10
[ 256417-10-4 ]
[ 1203662-96-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sulfuric acid; nitric acid; at 0 - 5℃; for 2.25h;	[0334] 5-Amino-4-(2-fluoro-4-iodo-phenylamino)-6-methoxy-indazole-l- carboxylic acid tert-butyl ester [0335] Step 1: 2,6-Difluoro-4-methoxy-3-nitro-benzaldehvde[0336] To a solution of cold (-50C) nitric acid (2.7 mL) was added concentrated sulfuric acid (1.75 mL, 32 mmoL) dropwise keeping the temperature below 50C. The solution was added to a cooled solution of <strong>[256417-10-4]2,6-difluoro-4-methoxy benzaldehyde</strong> (5.0 g, 29 mmoL) in sulfuric acid (20 mL) over 15 minutes keeping the temperature below 50C. After stirring at O0C for 2 hours the orange solution was poured on to ice, the white precipitate which formed was collected by filtration to give the title compound as a white solid (6.33 g, 100%). 1H NMR (CDCl3) 10.20 (1 H, t, J = 1.17 Hz), 6.69 (1 H, dd, J = 11.68, 1.93 Hz), 4.03 (3 H, s)

Reference： [1]Patent: WO2010/3025,2010,A1 .Location in patent: Page/Page column 80-81

11
[ 256417-10-4 ]
[ 1193353-98-8 ]

Reference： [1]Patent: US2011/45101,2011,A1
[2]Patent: WO2011/56463,2011,A2

12
[ 256417-10-4 ]
[ 1193354-58-3 ]

Reference： [1]Patent: US2011/45101,2011,A1
[2]Patent: WO2011/56463,2011,A2

13
[ 256417-10-4 ]
[ 1193580-64-1 ]

Reference： [1]Patent: US2011/45101,2011,A1
[2]Patent: WO2011/56463,2011,A2

14
[ 256417-10-4 ]
[ 1193512-02-5 ]

Reference： [1]Patent: US2011/45101,2011,A1
[2]Patent: WO2011/56463,2011,A2

15
[ 256417-10-4 ]
[ 1193354-78-7 ]

Reference： [1]Patent: US2011/45101,2011,A1
[2]Patent: WO2011/56463,2011,A2

16
[ 256417-10-4 ]
[ 1193350-43-4 ]

Reference： [1]Patent: US2011/45101,2011,A1
[2]Patent: WO2011/56463,2011,A2

17
[ 256417-10-4 ]
[ 1193350-51-4 ]

Reference： [1]Patent: US2011/45101,2011,A1
[2]Patent: WO2011/56463,2011,A2

18
[ 256417-10-4 ]
[ 691905-10-9 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1365 - 1378

19
[ 256417-10-4 ]
[ 691902-74-6 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1365 - 1378

20
[ 256417-10-4 ]
[ 691905-11-0 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1365 - 1378

21
[ 256417-10-4 ]
[ 691902-73-5 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1365 - 1378

22
[ 256417-10-4 ]
[ 1146782-92-4 ]

Reference： [1]Patent: WO2011/56463,2011,A2

23
[ 256417-10-4 ]
[ 4097-89-6 ]
tris(2,6-difluoro-4-methoxybenzyl)tren [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%		In a round bottom flask, tris(2-aminoethyl)amine (tren) (546mg, 3.74mmol) was dissolved in methanol (10mL) and ice-bath cooled. Then, a solution of <strong>[256417-10-4]2,6-difluoro-4-methoxybenzaldehyde</strong> (2.00g, 11.60mmol, 3.1eq) in a 1:1 (v/v) mixture of chloroform/methanol (10mL) was added drop-wise. The reaction was slowly warmed up to room temperature and stirred overnight. Methanol (10mL) was then added. Subsequent portions of NaBH4 (878mg, 23.20mmol) were added to the ice-cooled mixture over a thirty-minute period and the mixture was stirred for another hour. Solvents were evaporated. A solution of 10% NaOH in water was added (25mL), and the resulting mixture was extracted with toluene (3×30mL). The combined organic phases were extracted with HCl 1M (3×50mL) and the combined aqueous phases were then basified with an aqueous 10% NaOH solution. The solution was then extracted with toluene (3×100mL) and the organic layers were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give a pale yellow oil (1.88g, 82%).

Reference： [1]Catalysis Communications,2014,vol. 52,p. 26 - 30

24
[ 773837-37-9 ]
[ 256417-10-4 ]
[ 34985-37-0 ]
2-(2,6-difluoro-4-methoxyphenyl)-2-((2S)-2-methylbutylamino)acetonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%		To a solution of sodium bisulfite (1.71 g, 17 mmol) in a mixture of deionized water (32 mL) and methanol (3.0 mL) at room temperature was added <strong>[256417-10-4]2,6-difluoro-4-methoxybenzaldehyde</strong> (2.7 g, 16 mmol). The reaction mixture was stirred for 15 min, and sodium cyanide (0.81 g, 17 mmol) was added. The reaction mixture was stirred for an additional 20 min and cooled using an ice water bath. A solution of (S)-2-methylbutylamine (Sigma-Aldrich, 1.5 g, 17 mmol) in methanol (6.0 mL) was added over approximately 2 min, and the resulting reaction mixture was stirred at 0 C for 15 min and then heated to 35 C for 2 h. The resulting mixture was then extracted with ethyl acetate (2 * 40 mL), and the combined organic layers were washed with brine, dried (MgSO4) and concentrated to give 2-(2,6-difluoro-4-methoxy-phenyl)-2-((2S)-2-methylbutylamino)-acetonitrile (8c, 3.9 g, 15 mmol, 93%) as an oil. 1H NMR (CDCl3): delta 6.51 (m, 2H), 4.83 (br s, 1H), 3.80 (s, 3H), 2.76 (m, 1H), 2.52 (m, 1H), 1.49 (m, 2H), 1.17 (m, 1H), 0.90 (m, 6H).

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 435 - 443

25
[ 256417-10-4 ]
[ 1000197-92-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 435 - 443

26
[ 256417-10-4 ]
5-chloro-6-[2,6-difluoro-4-[3-(methylamino)propoxy]phenyl]-1-[(2S)-2-methylbutyl]-3-pyrazol-1-ylpyrazin-2-one hydrochloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 435 - 443

27
[ 256417-10-4 ]
5-chloro-6-[4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl]-1-[(2S)-2-methylbutyl]-3-pyrazol-1-ylpyrazin-2-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 435 - 443

28
[ 256417-10-4 ]
3,5-dichloro-6-(2,6-difluoro-4-methoxyphenyl)-1-((2S)-2-methylbutyl)-2(1H)-pyrazinone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 435 - 443

29
[ 256417-10-4 ]
5-chloro-6-(2,6-difluoro-4-methoxyphenyl)-1-((2S)-2-methylbutyl)-3-(1H-pyrazol-1-yl)-2(1H)-pyrazinone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 435 - 443

30
[ 256417-10-4 ]
5-chloro-6-(2,6-difluoro-4-hydroxyphenyl)-1-((2S)-2-methylbutyl)-3-(1H-pyrazol-1-yl)-2(1H)-pyrazinone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 435 - 443

31
[ 256417-10-4 ]
4-((4-(2,6-difluoro-4-methoxybenzoyl)pyrimidin-2-yl)amino)benzonitrile [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 122,p. 185 - 195

32
[ 256417-10-4 ]
4-((5-bromo-4-(2,6-difluoro-4-methoxybenzoyl)pyrimidin-2-yl)amino)benzonitrile [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 122,p. 185 - 195

33
[ 256417-10-4 ]
4-((5-bromo-4-(2,6-difluoro-4-hydroxybenzoyl)pyrimidin-2-yl)amino)benzonitrile [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 122,p. 185 - 195

34
[ 3934-20-1 ]
[ 256417-10-4 ]
(2-chloropyrimidin-4-yl)(2,6-difluoro-4-methoxyphenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With 1,3-dimethylbenzimidazolium Iodide; sodium hydride; In 1,4-dioxane; mineral oil; for 14h;Inert atmosphere; Heating;	Method A: Sodium hydride (60% dispersion in mineral oil, 1.2 g, 29 mmol) was added to a solution of 2,4-dichloropyrimidine (3 g,20 mmol), <strong>[256417-10-4]2,6-difluoro-4-methoxybenzaldehyde</strong> (4 g, 23 mmol) and N,N-dimethylbenzimidazolium iodide (1 g, 3.6 mmol) in anhydrous dioxane (50 mL). The reaction mixture was heated under argon at 90C for 14 h and poured into ice cold water. The product was extracted with EtOAc (2 x 100 mL). Organic phase was washed with brine (2 100 mL), dried over sodium sulphate and evaporated to dryness. Column chromatography on silica gel using gradient from 0% to 50% ethyl acetate in hexane afforded 13 (4.15 g, 73%) as yellowish powder. 1H NMR (600.1 MHz, DMSO-d6) delta 8.43 (d, J = 4.9 Hz, 1H, Py-H6), 7.33 (d, J = 4.9 Hz, 1H, Py-H5), 6.24 (dd, J = 1.6,12.1 Hz, 2H, Ar-meta), 3.19 (s, 3H, CH3); 13C NMR (150.9 MHz, DMSO-d6) delta 186.06 (CO), 164.59 (t, J = 15.0 Hz, Ar-para), 163.36 (Py-C6), 162.52 (Py-C4), 161.68 (dd, J = 10.0, 252.4 Hz, Ar-ortho), 160.02 (Py-C2), 117.70 (Py-C5), 106.64 (t, J = 17.9 Hz, Ar-ipso), 99.10 (dd, J = 3.5, 28.4 Hz, Ar-meta), 56.72 (OCH3); HRMS (ESI): Calculated for C12H8N2O2ClF2 [M+H]+: 285.02369, Found: 285.02372; UPLC/MS (m/z) 284.85 [M+H]+, Tr 4.10 min.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 122,p. 185 - 195

35
[ 256417-10-4 ]
[ 75-52-5 ]
(Ε)-1,3-difluoro-5-methoxy-2-(2-nitrovinyl)benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17.5 g	With ammonium acetate; In acetic acid; at 100℃; for 6h;Inert atmosphere;	Under an argon atmosphere, to a solution of <strong>[256417-10-4]2,6-difluoro-4-methoxybenzaldehyde</strong> (14.7 g) in acetic acid (85 mL) were added ammonium acetate (11.2 g) and nitromethane (22.9 mL) to produce a reaction solution. The reaction solution was stirred at 100oC for 6 hours. The reaction solution was concentrated under reduced pressure, water was added thereto, and the precipitated solid was collected by filtration and washed with water. The resulting solid was dried to obtain the title compound as a yellow solid (17.5 g).1HNMR(400 MHz, CDCl3) delta: 3.87 (3H, s), 6.54-6.59 (2H, m), 7.77 (1H, d, J = 13.4 Hz), 8.11 (1H, d, J = 13.4 Hz).

Reference： [1]Patent: WO2016/189876,2016,A1 .Location in patent: Paragraph 0332-0334

36
[ 617-84-5 ]
[ 372-18-9 ]
[ 93343-10-3 ]
[ 256417-10-4 ]
[ 437-81-0 ]

Reference： [1]Chemistry - A European Journal,2017,vol. 23,p. 10280 - 10284

37
[ 331-64-6 ]
[ 256417-10-4 ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 2789 - 2792

38
[ 256417-10-4 ]
methyl 4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidine-3-carboxylate [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

39
[ 256417-10-4 ]
diethyl 2-(aminomethyl)-3-(2,6-difluoro-4-methoxyphenyl)pentanedioate hydrochloride [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

40
[ 256417-10-4 ]
rac-trans-5-amino-4-(2,6-difluoro-4-methoxyphenyl)piperidin-2-one [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

41
[ 256417-10-4 ]
rac-trans-benzyl (4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidin-3-yl)carbamate [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

42
[ 256417-10-4 ]
diethyl 2-cyano-3-(2,6-difluoro-4-methoxyphenyl)pentanedioate [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

43
[ 256417-10-4 ]
rac-trans-tert-butyl (1-acetyl-4-(2,6-difluoro-4-methoxyphenyl)piperidin-3-yl)carbamate [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

44
[ 256417-10-4 ]
rac-trans-1-(3-amino-4-(2,6-difluoro-4-methoxyphenyl)piperidin-1-yl)ethanone hydrochloride [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

45
[ 256417-10-4 ]
rac-trans-1-(4-chlorophenyl)-3-(4-(2,6-difluoro-4-methoxyphenyl)piperidin-3-yl)urea [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

46
[ 256417-10-4 ]
rac-trans-5-amino-4-(2,6-difluoro-4-methoxyphenyl)piperidin-2-one hydrochloride [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1
[2]Patent: US2018/78541,2018,A1

47
[ 256417-10-4 ]
rac-trans-tert-butyl (1-(cyclopropylmethyl)-4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidin-3-yl)carbamate [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1
[2]Patent: US2018/78541,2018,A1

48
[ 256417-10-4 ]
rac-trans-5-amino-1-(cyclopropylmethyl)-4-(2,6-difluoro-4-methoxyphenyl)piperidin-2-one [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1
[2]Patent: US2018/78541,2018,A1

49
[ 256417-10-4 ]
rac-trans-ethyl 4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidine-3-carboxylate [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

50
[ 256417-10-4 ]
rac-trans-1-(4-chlorophenyl)-3-(1-(cyclopropanecarbonyl)-4-(2,6-difluoro-4-methoxyphenyl)piperidin-3-yl)urea [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

51
[ 256417-10-4 ]
rac-trans-1-(4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidin-3-yl)-3-(pyridin-4-yl)urea [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

52
[ 256417-10-4 ]
rac-trans-tert-butyl (4-(2,6-difluoro-4-methoxyphenyl)piperidin-3-yl)carbamate [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

53
[ 256417-10-4 ]
rac-trans-tert-butyl (4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidin-3-yl)carbamate [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1
[2]Patent: US2018/78541,2018,A1

54
[ 256417-10-4 ]
rac-trans-1-benzyl-4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidine-3-carboxylic acid [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

55
[ 256417-10-4 ]
rac-trans-4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidine-3-carboxylic acid [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

56
[ 256417-10-4 ]
trans-tert-butyl (4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidin-3-yl)carbamate [ No CAS ]
trans-tert-butyl (4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidin-3-yl)carbamate [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1
[2]Patent: US2018/78541,2018,A1

57
[ 256417-10-4 ]
rac-trans-tert-butyl (1-benzyl-4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidin-3-yl)carbamate [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

58
[ 256417-10-4 ]
rac-trans-1-(1-acetyl-4-(2,6-difluoro-4-methoxyphenyl)piperidin-3-yl)-3-(4-chlorophenyl)urea [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

59
[ 256417-10-4 ]
rac-trans-1-(1-acetyl-4-(2,6-difluoro-4-methoxyphenyl)piperidin-3-yl)-3-(4-bromophenyl)urea [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

60
[ 256417-10-4 ]
rac-trans-1-(4-bromophenyl)-3-(4-(2,6-difluoro-4-methoxyphenyl)piperidin-3-yl)urea [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

61
[ 256417-10-4 ]
trans-1-(4-chlorophenyl)-3-(4-(2,6-difluoro-4-methoxyphenyl)piperidin-3-yl)urea [ No CAS ]
trans-1-(4-chlorophenyl)-3-(4-(2,6-difluoro-4-methoxyphenyl)piperidin-3-yl)urea [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

62
[ 256417-10-4 ]
rac-trans-1-(4-chlorophenyl)-3-(4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidin-3-yl)urea [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1
[2]Patent: US2018/78541,2018,A1

63
[ 256417-10-4 ]
rac-trans-tert-butyl (1-benzyl-4-(2,6-difluoro-4-methoxyphenyl)piperidin-3-yl)carbamate [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

64
[ 256417-10-4 ]
rac-trans-1-(4-chlorophenyl)-3-(1-(cyclopropylmethyl)-4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidin-3-yl)urea [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1
[2]Patent: US2018/78541,2018,A1

65
[ 256417-10-4 ]
rac-trans-1-(4-chlorophenyl)-3-(4-(2,6-difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-6-oxopiperidin-3-yl)urea [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1
[2]Patent: US2018/78541,2018,A1

66
[ 256417-10-4 ]
rac-trans-methyl 2-(5-(3-(4-chlorophenyl)ureido)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopiperidin-1-yl)acetate [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1
[2]Patent: US2018/78541,2018,A1

67
[ 256417-10-4 ]
trans-1-(4-chlorophenyl)-3-(4-(2,6-difluoro-4-methoxyphenyl)piperidin-3-yl)urea [ No CAS ]
trans-1-(4-chlorophenyl)-3-(4-(2,6-difluoro-4-methoxyphenyl)piperidin-3-yl)urea [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

68
[ 256417-10-4 ]
trans-1-(4-chlorophenyl)-3-(1-(cyclopropanecarbonyl)-4-(2,6-difluoro-4-methoxyphenyl)piperidin-3-yl)urea [ No CAS ]
trans-1-(4-chlorophenyl)-3-(1-(cyclopropanecarbonyl)-4-(2,6-difluoro-4-methoxyphenyl)piperidin-3-yl)urea [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

69
[ 256417-10-4 ]
trans-1-(4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidin-3-yl)-3-(pyridin-4-yl)urea [ No CAS ]
trans-1-(4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidin-3-yl)-3-(pyridin-4-yl)urea [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

70
[ 256417-10-4 ]
trans-1-(4-chlorophenyl)-3-(4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidin-3-yl)urea [ No CAS ]
trans-1-(4-chlorophenyl)-3-(4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidin-3-yl)urea [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1
[2]Patent: US2018/78541,2018,A1

71
[ 256417-10-4 ]
rac-trans-1-(5-chlorothiophen-2-yl)-3-(4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidin-3-yl)urea [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

72
[ 256417-10-4 ]
rac-trans-ethyl 4-(2,6-difluoro-4-methoxyphenyl)-1-(4-methoxybenzyl)-6-oxopiperidine-3-carboxylate [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

73
[ 256417-10-4 ]
rac-trans-4-(2,6-difluoro-4-methoxyphenyl)-1-(4-methoxybenzyl)-6-oxopiperidine-3-carboxylic acid [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

74
[ 256417-10-4 ]
rac-trans-tert-butyl (4-(2,6-difluoro-4-methoxyphenyl)-1-(4-methoxybenzyl)-6-oxopiperidin-3-yl)carbamate [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

75
[ 256417-10-4 ]
rac-trans-ethyl 1-benzyl-4-(2,6-difluoro-4-methoxyphenyl)-6-oxopiperidine-3-carboxylate [ No CAS ]

Reference： [1]Patent: US2018/78541,2018,A1

76
[ 256417-10-4 ]
[ 105-56-6 ]
(E)-ethyl 2-cyano-3-(2,6-difluoro-4-methoxyphenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With triethylamine; In ethanol; at 60℃; for 8h;	Step1 A stirred solution of <strong>[256417-10-4]2,6-difluoro-4-methoxybenzaldehyde</strong> (50.0 g, 0.290 mol) in EtOH (500 mL) was charged with ethyl 2-cyanoacetate (39.4 g, 0.348 mol) and TEA (48.4 mL, 0.348 mol) at RT. The resulting solution was heated at 60 C. for 8 h. Upon reaction completion, the reaction mixture was cooled to RT and concentrated under reduced pressure. The crude product was dissolved in EtOAc (250 mL) and washed with water (2*150 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford (E)-ethyl 2-cyano-3-(2,6-difluoro-4-methoxyphenyl)acrylate (50.0 g, 64%) as a yellow solid (TLC system: 30% EtOAc in pet ether; Rf: 0.5).

Reference： [1]Patent: US2018/78541,2018,A1 .Location in patent: Paragraph 0290; 0292

77
[ 256417-10-4 ]
(4-amino-1-tributylstannanylbutyl)carbamic acid tert-butyl ester [ No CAS ]
tert-butyl (4-((2,6-difluoro-4-methoxybenzylidene)amino)-1-(tributylstannyl)butyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	In dichloromethane; at 20℃; for 16h;Molecular sieve;	To a stirred solution of 4-amino-1-tributylstannanyl-butyl)-carbamic acid tert-butyl ester (1 eq) in DCM (8 mL/mmol) was added 4-methoxybenzaldehyde (1 eq) followed by the addition of MS 4 powder (120 mg/mmol) and the reaction mixture was stirred at RT for a period of 16 h. After completion of the reaction the reaction mass was filtered through a short layer of celite pad and concentrated under reduced pressure to get the corresponding tert-butyl (4-((2,6-difluoro-4-methoxybenzylidene)amino)-1-(tributylstarmyl)butyl)carbamate as a colorless sticky solid (quantitative yield).

Reference： [1]Patent: US2018/78541,2018,A1 .Location in patent: Page/Page column 0411-0413

78
[ 256417-10-4 ]
[ 5927-18-4 ]
(E)-methyl 3-(2,6-difluoro-4-methoxyphenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃; for 24h;	Step1 To a stirred solution of <strong>[256417-10-4]2,6-difluoro-4-methoxybenzaldehyde</strong> (5 g, 29.05 mmol, 1 eq) in THF (100 mL) was added trimethylphosphonoacetate (5.03 mL, 34.86 mmol, 1.2eq) and DBU (5.65 mL, 37.76 mmol, 1.3eq). The solution was stirred at RT for 24 h. It was then concentrated in vacuo and dissolved in 1:2 EtOAc/Hexane (250 mL). The resulting solution was washed sequentially with 1 N aq. HCl (100 mL), saturated aqueous NaHCO3 (100 mL) and finally with brine (100 mL). The organic phase was then dried over sodium sulfate, filtered and evaporated under reduced pressure to yield the crude (E)-methyl 3-(2,6-difluoro-4-methoxyphenyl)acrylate as off white solid (5.8 g, 87%). It was used for the next step without further purification.

Reference： [1]Patent: US2018/78541,2018,A1 .Location in patent: Paragraph 0355; 0357

79
[ 256417-10-4 ]
2-amino-N-trityloxy-acetamide [ No CAS ]
2-[(2,6-difluoro-4-methoxy-phenyl)methylamino]-N-trityloxy-acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 4578 - 4592

80
[ 256417-10-4 ]
C₁₀H₁₆O₂ [ No CAS ]
(1R,3S,6R,7S,9R)-6-(2,6-difluoro-4-methoxyphenyl)-1,3-dimethyl-5-oxatricyclo[5.3.0.03,9]decan-2-one [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 9291 - 9298

81
[ 256417-10-4 ]
[ 149-73-5 ]
2-(dimethoxymethyl)-1,3-difluoro-5-methoxybenzene [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 9291 - 9298

82
[ 256417-10-4 ]
(1R,3S,6R,7S,9R)-6-(2,6-difluoro-4-methoxyphenyl)-1,3-dimethyl-5-oxatricyclo[5.3.0.03,9]decan-2-one [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 9291 - 9298

83
[ 256417-10-4 ]
(3S,4R)-ethyl 4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/227067,2018,A1

84
[ 256417-10-4 ]
(3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/227067,2018,A1

85
[ 256417-10-4 ]
N-((3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)-1H-imidazole-1-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/227067,2018,A1

86
[ 256417-10-4 ]
benzyl (-)-[(3S^*,4R^*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]carbamate [ No CAS ]

Reference： [1]Patent: WO2018/227067,2018,A1

87
[ 256417-10-4 ]
(3S,4R)-3-amino-4-(2,6-difluoro-4-methoxyphenyl)pyrrolidin-2-one [ No CAS ]

Reference： [1]Patent: WO2018/227067,2018,A1
[2]Patent: WO2018/227067,2018,A1

88
[ 256417-10-4 ]
(Ε)-1,3-difluoro-5-methoxy-2-(2-nitrovinyl)benzene [ No CAS ]

Reference： [1]Patent: WO2018/227067,2018,A1

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P234	Keep only in original container.
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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

Ghs Hazard Statements

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