[ CAS No. 172921-33-4 ]

Name: 172921-33-4|1-Bromo-4-chloro-2,5-difluorobenzene|97%
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Quality Control of [ 172921-33-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 172921-33-4 ]

SDS Specification

Alternatived Products of [ 172921-33-4 ]

Product Details of [ 172921-33-4 ]

CAS No. :	172921-33-4	MDL No. :	MFCD09878116
Formula :	C₆H₂BrClF₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QVXGDUWCYGGRHC-UHFFFAOYSA-N
M.W :	227.43	Pubchem ID :	23270179
Synonyms :

Calculated chemistry of [ 172921-33-4 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	39.07
TPSA :	0.0 Å²

Pharmacokinetics

GI absorption :	Low
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) :	-5.24 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.25
Log Po/w (XLOGP3) :	3.44
Log Po/w (WLOGP) :	4.22
Log Po/w (MLOGP) :	4.48
Log Po/w (SILICOS-IT) :	4.02
Consensus Log Po/w :	3.68

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.86
Solubility :	0.0313 mg/ml ; 0.000138 mol/l
Class :	Soluble
Log S (Ali) :	-3.12
Solubility :	0.172 mg/ml ; 0.000757 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.43
Solubility :	0.00843 mg/ml ; 0.0000371 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.95

Safety of [ 172921-33-4 ]

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 [ 172921-33-4 ]

* 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 [ 172921-33-4 ]
Downstream synthetic route of [ 172921-33-4 ]

[ 172921-33-4 ] Synthesis Path-Upstream 1~1

1
[ 2613-30-1 ]
[ 172921-33-4 ]

Yield	Reaction Conditions	Operation in experiment
48.4%	With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 20 - 65℃;	Anhydrous copper (II) bromide (2.7 g, 12.1 mmol) and t-butyl nitrite (1.56 g, 15.1 mmol) were combined in anhydrous acetonitrile (25 mL). The resulting mixture was heated to 65° C. and a solution of 4-chloro-2,5-difluoro-phenylamine (1.65 g, 10.1 mmol) in anhydrous acetonitrile (2 mL) was added dropwise (vigorous gas evolution was noted). After the reaction mixture cooled to ambient temperature, it was added to 2N HCl and extracted twice with diethyl ether. The organic extracts were then combined, washed with 2N HCl, washed with saturated sodium bicarbonate, dried, concentrated and purified by flash chromatography on silica gel (hexanes) to give the title compound as a white solid (1.11 g, 48.4percent yield): ¹H NMR (CDCl₃) δ 7.38 (dd, 2H), 7.21 (dd, 2H).
48.4%	With tert.-butylnitrite; copper(ll) bromide In acetonitrile	2. Preparation of 1-Bromo-4-chloro-2,5-difluorobenzene Anhydrous copper (II) bromide (2.7 g, 12.1 mmol) and t-butyl nitrite (1.56 g, 15.1 mmol) were combined in anhydrous acetonitrile (25 mL). The resulting mixture was heated to 65° C. and a solution of 4-chloro-2,5-difluoro-phenylamine (1.65 g, 10.1 mmol) in anhydrous acetonitrile (2 mL) was added dropwise (vigorous gas evolution was noted). After the reaction mixture cooled ambient temperature, it was added to 2N HCl and extracted with ether twice. The organic extracts were then combined, washed with 2N HCl, washed with saturated sodium bicarbonate, dried, concentrated and purified by flash chromatography on silica gel (hexanes) to give the title compound as a white solid (1.11 g, 48.4percent yield): ¹H NMR (CDCl₃): δ 7.38 (dd, 2H), 7.21 (dd, 2H).

Reference： [1] Patent: US2009/88322, 2009, A1, . Location in patent: Page/Page column 8
[2] Patent: US2009/62125, 2009, A1, . Location in patent: Page/Page column 8

[ 172921-33-4 ] Synthesis Path-Downstream 1~19

1
[ 61676-62-8 ]
[ 172921-33-4 ]
[ 1126320-24-8 ]

Yield	Reaction Conditions	Operation in experiment
72.3%		<strong>[172921-33-4]1-Bromo-4-chloro-2,5-difluorobenzene</strong> (1.11 g, 4.9 mmol) was dissolved in tetrahydrofuran (THF; 15 mL) and cooled to -10° C. A 2.0M solution of isopropyl-magnesium chloride (2.7 mL, 5.4 mmol) in THF was added dropwise via syringe. The reaction mixture was stirred at -10° C. for 1 h, allowed to warm toward 0° C. for 1 h, then cooled again to -10° C. A solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 5.4 mmol) in THF (1.0 mL) was then added dropwise and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was then added to diethyl ether and extracted with 1N sodium hydroxide twice. The aqueous phases were combined, acidified to pH 3 with concentrated HCl, and extracted with dichloromethane twice. The organic phases were combined, dried, filtered and concentrated to give the title compound (0.97 g, 72.3percent yield) that was used without further purification: 1H NMR (CDCl3) delta 7.45 (dd, 1H), 7.09 dd, 1H), 1.36 (s, 12H).
62%		To a solution of l-bromo-4-chloro-2,5-difluorobenzene (200 mg, 0.879 mmol) in THF (10 mL) cooled to -10 0 C was added isopropylmagnesium bromide (1M in THF, 1.055 mL, 1.055 mmol) dropwise and the reaction mixture was stirred at this temperature for 1 h. The reaction mixture was then warmed to 0 °C and stirred for another 1 h. The resultant mixture was again cooled to -10 °C and treated dropwise with a solution of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (196 mg, 1.055 mmol). The reaction mixture was allowed to warm up to room temperature and treated with a saturated solution of ammonium chloride (3 mL). The layers were separated and aqueous layer was extracted with dichloromethane (2 x 2 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude compound which was purified by column chromatography on a silica (7:3 - Ethyl acetate :hexane) to afford 2-(4- chloro-2,5-difluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (150 mg, 0.546 mmol, 62percent yield) as an oil. 1H NMR (400 MHz, DMSO-d6) delta ppm 7.46 - 7.49 (m, 1H), 7.09 - 7.13 (m, 1 H), 1.35 (s, 12H).
62%		To a solution of <strong>[172921-33-4]1-bromo-4-chloro-2,5-difluorobenzene</strong> (200 mg, 0.879 mmol) in THF (10 mL) cooled to -10°C was added isopropylmagnesium bromide (1M in THF, 1.055 mL, 1.055 mmol) dropwise and the reaction mixture was stirred at this temperature for 1 h. The reaction mixture was then warmed to 0 °C and stirred for another 1 h. The resultant mixture was again cooled to -10 °C and treated dropwise with a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (196 mg, 1.055 mmol). The reaction mixture was allowed to warm up to room temperature and treated with a saturated solution of ammonium chloride (3 mL). The layers were separated and aqueous layer was extracted with dichloromethane (2x2 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude compound which was purified by column chromatography on a silica (7:3 - Ethyl acetate:hexane) to afford 2-(4-chloro-2,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (150 mg, 0.546 mmol, 62percent yield) as an oil.

3. Preparation of 2-(4-Chloro-2,5-difluorophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane <strong>[172921-33-4]1-Bromo-4-chloro-2,5-difluorobenzene</strong> (1.11 g, 4.9 mmol) was dissolved in tetrahydrofuran (THF; 15 mL) and cooled to -10° C. A 2.0M solution of isopropyl-magnesium chloride (2.7 mL, 5.4 mmol) in THF was added dropwise via a syringe. The reaction mixture was stirred at -10° C. for 1 hour, allowed to warm toward 0° C. for 1 hour, then cooled to -10° C. again. A solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 5.4 mmol) in THF (1.0 mL) was then added dropwise and the reaction was allowed to warm to ambient temperature. The reaction mixture was then added to diethyl ether and extracted with 1N sodium hydroxide twice. The aqueous phases were combined, acidified to pH 3 with concentrated HCl, and extracted with dichloromethane twice. The organic phases were combined, dried, filtered and concentrated to give the title compound (0.97 g, 72.3percent yield) that was used without further purification: 1H NMR (CDCl3): delta 7.45 (dd, 1H), 7.09 dd, 1H), 1.36 (s, 12H).

Reference： [1]Patent: US2009/88322,2009,A1 .Location in patent: Page/Page column 8
[2]Patent: WO2015/116060,2015,A1 .Location in patent: Page/Page column 83-84
[3]Patent: JP2015/528018,2015,A .Location in patent: Paragraph 0176
[4]Patent: US2009/62125,2009,A1 .Location in patent: Page/Page column 8-9

2
[ 2613-30-1 ]
[ 172921-33-4 ]

Yield	Reaction Conditions	Operation in experiment
48.4%	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20 - 65℃;	Anhydrous copper (II) bromide (2.7 g, 12.1 mmol) and t-butyl nitrite (1.56 g, 15.1 mmol) were combined in anhydrous acetonitrile (25 mL). The resulting mixture was heated to 65° C. and a solution of 4-chloro-2,5-difluoro-phenylamine (1.65 g, 10.1 mmol) in anhydrous acetonitrile (2 mL) was added dropwise (vigorous gas evolution was noted). After the reaction mixture cooled to ambient temperature, it was added to 2N HCl and extracted twice with diethyl ether. The organic extracts were then combined, washed with 2N HCl, washed with saturated sodium bicarbonate, dried, concentrated and purified by flash chromatography on silica gel (hexanes) to give the title compound as a white solid (1.11 g, 48.4percent yield): 1H NMR (CDCl3) delta 7.38 (dd, 2H), 7.21 (dd, 2H).
48.4%	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile;	2. Preparation of 1-Bromo-4-chloro-2,5-difluorobenzene Anhydrous copper (II) bromide (2.7 g, 12.1 mmol) and t-butyl nitrite (1.56 g, 15.1 mmol) were combined in anhydrous acetonitrile (25 mL). The resulting mixture was heated to 65° C. and a solution of 4-chloro-2,5-difluoro-phenylamine (1.65 g, 10.1 mmol) in anhydrous acetonitrile (2 mL) was added dropwise (vigorous gas evolution was noted). After the reaction mixture cooled ambient temperature, it was added to 2N HCl and extracted with ether twice. The organic extracts were then combined, washed with 2N HCl, washed with saturated sodium bicarbonate, dried, concentrated and purified by flash chromatography on silica gel (hexanes) to give the title compound as a white solid (1.11 g, 48.4percent yield): 1H NMR (CDCl3): delta 7.38 (dd, 2H), 7.21 (dd, 2H).

Reference： [1]Patent: US2009/88322,2009,A1 .Location in patent: Page/Page column 8
[2]Patent: US2009/62125,2009,A1 .Location in patent: Page/Page column 8

3
[ 172921-33-4 ]
(S)-8-((2-amino-4-methylpentyl)oxy)-9-fluoro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one [ No CAS ]