[ CAS No. 1204296-03-6 ] {[proInfo.proName]}

Name: 1204296-03-6|2-Chloro-4-(difluoromethyl)pyridine|97%
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SKU: A277545
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Quality Control of [ 1204296-03-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1204296-03-6 ]

SDS Specification

Alternatived Products of [ 1204296-03-6 ]

Product Details of [ 1204296-03-6 ]

CAS No. :	1204296-03-6	MDL No. :	MFCD14525492
Formula :	C₆H₄ClF₂N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CQNIYQCVDLBGPY-UHFFFAOYSA-N
M.W :	163.55	Pubchem ID :	45790949
Synonyms :

Calculated chemistry of [ 1204296-03-6 ]

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 :	34.31
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) :	-5.57 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.68
Log Po/w (XLOGP3) :	2.43
Log Po/w (WLOGP) :	3.19
Log Po/w (MLOGP) :	2.01
Log Po/w (SILICOS-IT) :	2.86
Consensus Log Po/w :	2.44

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.76
Solubility :	0.282 mg/ml ; 0.00173 mol/l
Class :	Soluble
Log S (Ali) :	-2.34
Solubility :	0.742 mg/ml ; 0.00453 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.24
Solubility :	0.0945 mg/ml ; 0.000578 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.55

Safety of [ 1204296-03-6 ]

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

Application In Synthesis of [ 1204296-03-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 1204296-03-6 ]
Downstream synthetic route of [ 1204296-03-6 ]

[ 1204296-03-6 ] Synthesis Path-Upstream 1~1

1
[ 101066-61-9 ]
[ 1204296-03-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	With diethylamino-sulfur trifluoride In dichloromethane at 0 - 20℃;	Example 7: Preparation of 2-chloro-4-(difluoromethyl)pyridine 2-Chloropyridine-4-carbaldehyde (990mg, 7.0mM) was dissolved in dichloromethane (40ml_) with stirring and the solution cooled to 0-5°C. Diethylamino sulfurtrifluoride (2.82g, 2.31 ml, 17.5mM) was added drop-wise over 15 minutes, keeping the reaction temperature below 5°C. The solution was stirred in the cold for 2 hours, allowed to warm slowly to room temperature and stood overnight. The reaction mixture was gradually added to saturated sodium hydrogen carbonate solution (30ml_) and ice (100ml_), making sure that the pH of the solution was >7 at all times. After 30 minutes the mixture was diluted with dichloromethane (30ml_) and water (20ml_) and the organic phase separated. The aqueous phase was further extracted with dichloromethane (2 x 20ml_). The organic extracts were combined, washed with water, dried over magnesium sulfate, filtered and the filtrate evaporated giving a yellow liquid which was chromatographed to give 2- chloro-4-(difluoromethyl)pyridine as a colourless liquid (813mg, 71 percent) H NMR (CDCI₃): δ 8.54 (d, 1 H); 7.81 (dd, 1 H); 7.45 (d, 1 H); 6.71 (t, 1 H)
71%	With diethylamino-sulfur trifluoride In dichloromethane at 0 - 20℃;	2-Chloropyridine-4-carbaldehyde (990mg, 7.0mM) was dissolved in dichloromethane (4OmL) with stirring and the solution cooled to 0-5°C. Diethylamino sulfurtrifluoride (2.82g, 2.31 ml, 17.5mM)was added drop-wise over 15 minutes, keeping the reaction temperature below 5°C. The solution was stirred in the cold for 2 hours, allowed to warm slowly to room temperature and stood overnight. The reaction mixture was gradually added to saturated sodium hydrogen carbonate solution (3OmL) and ice (lOOmL), making sure that the pH of the solution was >7 at all times. After 30 minutes the mixture was diluted with dichloromethane (3OmL) and water (2OmL) and theorganic phase separated. The aqueous phase was further extracted with dichloromethane (2 x2OmL). The organic extracts were combined, washed with water, dried over magnesium sulfate, filtered and the filtrate evaporated giving a yellow liquid which was chromatographed to give 2-chloro-4-(difluoromethyl)pyridine as a colourless liquid (813mg, 71 percent)1H NMR (CDCI3): ö 8.54 (d, 1H); 7.81 (dd, 1H); 7.45 (d, 1H); 6.71 (t, 1H)
60.6%	With diethylamino-sulfur trifluoride In dichloromethane at 0 - 20℃; for 12 h; Inert atmosphere	DAST (20.53 mL, 155.42 mmol) was added dropwise to 2-chloroisonicotinaldehyde (10 g, 70.64 mmol) in DCM (150 mL) at 0°C over a period of 10 minutes under nitrogen. The temperature was increased to room temperature and stirred for 12 hours. The reaction mixture was quenched and adjusted to pH 7-8 with saturated NaHC0₃ at 0°C. The aqueous phase was extracted with DCM (3 x 150 mL), the organic phases dried over Na₂S04, filtered and evaporated to afford yellow oil. The crude product was purified by flash silica chromatography, elution gradient 5 to 10percent EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 2-chloro-4-(dif uoromethyl)pyridine (Intermediate 86; 7.00 g, 60.6percent) as a yellow oil. H NMR (400 MHz, CDC1 , 20.5 °C) δ 6.65 (1H, t), 7.38 (1H, dd), 7.49 (1H, s), 8.55 (1H, dd). m/z (ES+), [M+H]+ = 164.

Reference： [1] Patent: WO2015/18432, 2015, A1, . Location in patent: Page/Page column 54
[2] Patent: WO2015/18431, 2015, A1, . Location in patent: Page/Page column 61; 62
[3] Patent: WO2017/80979, 2017, A1, . Location in patent: Page/Page column 175
[4] Patent: WO2016/95204, 2016, A1, . Location in patent: Page/Page column 52; 53

[ 1204296-03-6 ] Synthesis Path-Downstream 1~84

2
[ 1204296-03-6 ]
[ 73895-98-4 ]
[ 1411772-41-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; for 2.0h;Reflux;	Intermediate 12. 6-Bromo-N-[4-(difluoromethyl)pyridin-2-yl]-4-methylpyridin-2-amine; Potassium t-butoxide (1.0 M in THF, 198 mL, 198 mmol) was added to a solution of 6-bromo-4- methyl pyridine-2-amine (37 g, 198 mmol) and 2-chloro-4-(difiuoromethyl)pyridine (42.1 g, 257 mmol) in THF (60 mL) at 0 C. The resulting mixture was heated to reflux for 30 minutes then cooled to 0 C, and a second portion of potassium /-butoxide (1.0 M in THF, 80 mL, 80 mmol) was added. The mixture was again heated to reflux for 30 minutes, cooled to 0 C, and a third portion of potassium t-butoxide (1.0 M in THF, 80 mL, 80 mmol) was added. The mixture was again heated to reflux for 30 minutes. After cooling to 0 C, a fourth portion of potassium t- butoxide (1.0 M in THF, 20 mL, 20 mmol) was added. Upon refluxing for 30 minutes, the reaction was allowed to cool to room temperature, then diluted with saturated aqueous NH4C1 (500 mL) and diluted with DCM (500 mL). The layers were separated, and the aqueous layer was extracted a second time with DCM (500 mL). The combined organic layers were dried with Na2S04, filtered through a pad of CELITE (150 g), and concentrated in vacuo. The residue was triturated with DCM (100 mL), filtered, and washed with hexanes (2 x 50 mL) to afford one portion of 6-bromo-N-[4-(difluoromethyl)pyridin-2-yl]-4-methylpyridin-2-amine. The filtrate was concentracted, absorbed on silica gel and purified via silica gel column chromatography (EtOAc/Hex) to afford a second portion of 6-bromo-N-[4-(difluoromethyl)pyridin-2-yl]-4- methylpyridin-2-amine. MS ESI calc'd. for CnHnBrFaNs [M+H]+ 314 and 316, found 314 and 316. 1H NMR (600 MHz, DMSO-de) delta 10.20 (s, 1H), 8.35 (d, J= 5.1 Hz, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.01 (d, J = 5.1 Hz, 1H), 6.96 (t, J= 22.3 Hz, 1H), 6.95 (s, 1H), 2.24 (s, 3H).
	With potassium tert-butylate; In tetrahydrofuran; for 2.0h;Reflux;	Potassium t-butoxide (1.0 M in THF, 198 mL, 198 mmol) was added to a solution of 6-bromo-4- methyl pyridine-2-amine (37 g, 198 mmol) and 2-chloro-4-(difluoromethyl)pyridine (42.1 g, 257 mmol) in THF (60 mL) at 0 C. The resulting mixture was heated to reflux for 30 minutes then cooled to 0 C, and a second portion of potassium t-butoxide (1.0 M in THF, 80 mL, 80 mmol) was added. The mixture was again heated to reflux for 30 minutes, cooled to 0 C, and a third portion of potassium r-butoxide (1.0 M in THF, 80 mL, 80 mmol) was added. The mixture was again heated to reflux for 30 minutes. After cooling to 0 C, a fourth portion of potassium t- butoxide (1.0 M in THF, 20 mL, 20 mmol) was added. Upon refluxing for 30 minutes, the reaction was allowed to cool to room temperature, then diluted with saturated aqueous NH4CI (500 mL) and diluted with DCM (500 mL). The layers were separated, and the aqueous layer was extracted a second time with DCM (500 mL). The combined organic layers were dried with Na2S0 , filtered through a pad of CELITE (150 g), and concentrated in vacuo. The residue was triturated with DCM (100 mL), filtered, and washed with hexanes (2 x 50 mL) to afford one portion of 6-bromo-N-[4-(difluoromemyl)pyridm-2-yl]-4-memylpyridm-2-amine. The filtrate was concentracted, absorbed on silica gel and purified via silica gel column chromatography (EtOAc/Hex) to afford a second portion of 6-bromo-N-[4-(difluoromemyl)pyridin-2-yl]-4- methylpyridin-2-amine. MS ESI calc'd. for C12HnBrF2N3 [M+H]+314 and 316, found 314 and 316. 1H MR (600 MHz, DMSO-de) delta 10.20 (s, 1H), 8.35 (d, J= 5.1 Hz, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.01 (d, J= 5.1 Hz, 1H), 6.96 (t, J= 22.3 Hz, 1H), 6.95 (s, 1H), 2.24 (s, 3H).
	With potassium tert-butylate; In tetrahydrofuran; for 2.0h;Reflux;	Potassium ?-butoxide (1.0 M in THF, 198 mL, 198 mmol) was added to a solution of 6-bromo-4-methyl pyridine-2 -amine (37 g, 198 mmol) and 2-chloro-4- (difluoromethyl)pyridine (42.1 g, 257 mmol) in THF (60 mL) at 0 C. The resulting mixture was heated to reflux for 30 minutes then cooled to 0 C, and a second portion of potassium ?-butoxide (1.0 M in THF, 80 mL, 80 mmol) was added. The mixture was again heated to reflux for 30 minutes, cooled to 0 C, and a third portion of potassium ?-butoxide (1.0 M in THF, 80 mL, 80 mmol) was added. The mixture was again heated to reflux for 30 minutes. After cooling to 0 C, a fourth portion of potassium ?-butoxide (1.0 M in THF, 20 mL, 20 mmol) was added. Upon refluxing for 30 minutes, the reaction was allowed to cool to room temperature, then was diluted with saturated aqueous NH4C1 solution (500 mL) and DCM (500 mL). The layers were separated, and the aqueous layer was extracted a second time with DCM (500 mL). The combined organic layers were dried with sodium sulfate, filtered through a pad of CELITE (150 g), and concentrated under reduced pressure. The residue was triturated with DCM (100 mL), filtered, and washed with hexanes (2 x 50 mL) to afford one portion of 6-bromo-N-[4- (difluoromethyl)pyridin-2-yl]-4-methylpyridin-2-amine. The filtrate was concentracted, absorbed on silica gel and purified via silica gel column chromatography (ethyl acetate/Hex) to afford a second portion of 6-bromo-N-[4-(difluoromethyl)pyridin-2-yl]-4-methylpyridin-2- amine. MS ESI calc'd. for Ci2HnBrF2 3 [M+H]+ 314 and 316, found 314 and 316. XH NMR (600 MHz, DMSO-d6) delta 10.20 (s, 1H), 8.35 (d, J= 5.1 Hz, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.01 (d, J= 5.1 Hz, 1H), 6.96 (t, J= 22.3 Hz, 1H), 6.95 (s, 1H), 2.24 (s, 3H).

Reference： [1]Patent: WO2012/154518,2012,A1 .Location in patent: Page/Page column 46-47
[2]Patent: WO2012/154520,2012,A1 .Location in patent: Page/Page column 41
[3]Patent: WO2014/74421,2014,A1 .Location in patent: Page/Page column 46

3
[ 1204296-03-6 ]
methyl trans-4-[(1R or 1S)-(6-[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3'-bipyridin-6'-yl)-1-hydroxyethyl]cyclohexanecarboxylate [ No CAS ]

Reference： [1]Patent: WO2012/154518,2012,A1

4
[ 1204296-03-6 ]
trans-4-[(1R or 1S)-(6-[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3'-bipyridin-6'-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid [ No CAS ]

Reference： [1]Patent: WO2012/154518,2012,A1

5
[ 1204296-03-6 ]
methyl trans-4-[(1R or 1S)-(6-[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3'-bipyridin-6'-yl)-1-fluoroethyl]cyclohexanecarboxylate [ No CAS ]

Reference： [1]Patent: WO2012/154518,2012,A1

6
[ 1204296-03-6 ]
trans-4-[(1R or 1S)-(6-[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3'-bipyridin-6'-yl)-1-fluoroethyl]cyclohexanecarboxylic acid [ No CAS ]

Reference： [1]Patent: WO2012/154518,2012,A1

7
[ 1204296-03-6 ]
trans-4-[(1R or 1S)-(3-bromo-6-[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3'-bipyridin-6'-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid [ No CAS ]

Reference： [1]Patent: WO2012/154518,2012,A1

8
[ 1204296-03-6 ]
sodium trans-4-[(1R or 1S)-(6-[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3'-bipyridin-6'-yl)-1-hydroxyethyl]cyclohexanecarboxylate [ No CAS ]

Reference： [1]Patent: WO2012/154518,2012,A1

9
[ 1204296-03-6 ]
2-hydroxyethyl trans-4-[(1R or 1S)-(6-[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3'-bipyridin-6'-yl)-1-hydroxyethyl]cyclohexanecarboxylate [ No CAS ]

Reference： [1]Patent: WO2012/154518,2012,A1

10
[ 1204296-03-6 ]
(1R or 1S)-1-(6-[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3-bipyridin-6'-yl)-1-[trans-4-(hydroxymethyl)cyclohexyl]ethanol [ No CAS ]

Reference： [1]Patent: WO2012/154518,2012,A1

11
[ 1204296-03-6 ]
[ 1609977-34-5 ]