[ CAS No. 259860-08-7 ] {[proInfo.proName]}

Name: 259860-08-7|6-Bromo-5-fluoro-1H-indole|95%
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SKU: A116005
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Quality Control of [ 259860-08-7 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 259860-08-7 ]

CAS No. :	259860-08-7	MDL No. :	MFCD10000894
Formula :	C₈H₅BrFN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OIUXEDBYFWPCLF-UHFFFAOYSA-N
M.W :	214.03	Pubchem ID :	22262922
Synonyms :

Calculated chemistry of [ 259860-08-7 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	45.96
TPSA :	15.79 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) :	-5.59 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.9
Log Po/w (XLOGP3) :	2.84
Log Po/w (WLOGP) :	3.49
Log Po/w (MLOGP) :	2.73
Log Po/w (SILICOS-IT) :	3.62
Consensus Log Po/w :	2.92

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.56
Solubility :	0.0587 mg/ml ; 0.000274 mol/l
Class :	Soluble
Log S (Ali) :	-2.83
Solubility :	0.317 mg/ml ; 0.00148 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.42
Solubility :	0.00812 mg/ml ; 0.0000379 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.74

Safety of [ 259860-08-7 ]

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 [ 259860-08-7 ]

* 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 [ 259860-08-7 ]
Downstream synthetic route of [ 259860-08-7 ]

[ 259860-08-7 ] Synthesis Path-Upstream 1~4

1
[ 1034894-73-9 ]
[ 259860-08-7 ]

Yield	Reaction Conditions	Operation in experiment
89%	With iron; acetic acid In ethanol at 90℃;	The enamine (1.89 g, 4.38 mmol) was dissolved in EtOH (35.0 ml_). To this solution Fe (4.42 g, 79.0 mmol) and acetic acid (35.0 ml_) were added and the mixture was stirred at 90 ^°C for overnight. The resulting mixture was filtered and concentrated. The residue was purified by column chromatography (ethyl acetate-hexane; 1 :9) to afford 6- bromo-5-fluoro-1 H-indole as a yellow solid (0.83 g, 89percent). ¹H NMR (CDCI₃, 400 MHz): 6.52 (m, 1 H), 7.27 (m, 1 H), 7.38 (d, J = 9.3 Hz, 1 H), 7.57 (d, J = 5.7 Hz, 1 H), 8.18 (br. s, 1 H).
61%	With hydrazine In tetrahydrofuran; methanol at 20℃;	Synthesis of 6-Bromo-5-fluoroindole was carried out in this step according to the procedure reported by A. D. Batcho and W. Leimgruber; Org. Synth. 1985, 63, 214. A mixture of hydrazine hydrate (1.30 ml, 26.8 mmoles), crude [2-(4-Bromo-5-fluoro-2-nitro-phenyl)-vinyl]-dimethyl-amine as from step 2 and Raney nickle in tetrahydrofuran (30 ml) and methanol (30 ml) was stirred at room temperature over night. The catalyst was removed by filtration through celite and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 0.1N hydrogen chloride solution. The organic extract was washed with brine, dried (anhydrous sodium sulfate), and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluding with 10percent ethyl acetate in hexane to give 6-Bromo-5-fluoro-1H-indole as a light green solid (0.865 g, 61percent). ¹H NMR (CDCl₃) d: 6.49-6.51 (m, 1H), 7.23-7.26 (m, 1H), 7.36 (d, 1H, J=9.2 Hz), 7.56 (dd, 1H, J=5.6 Hz, 0.9 Hz), 8.14 (bs, 1H).

Reference： [1] Patent: WO2008/77138, 2008, A1, . Location in patent: Page/Page column 77
[2] Patent: US2004/224973, 2004, A1, . Location in patent: Page 22

2
[ 4637-24-5 ]
[ 224185-19-7 ]
[ 259860-08-7 ]

Yield	Reaction Conditions	Operation in experiment
16%	With hydrazine hydrate In tetrahydrofuran; methanol; N,N-dimethyl-formamide	6-Bromo-5-fluoroindole N,N-Dimethylformamide dimethylacetal (8.5 mL, 60 mmol) was added in one portion to a stirred solution of 3-bromo-4-fluoro-6-methylnitrobenzene (11.8 g, 50 mmol) in N,N-dimethylformamide (30 mL) at room temperature under Ar. The mixture was heated to 120° C., stirred for 16 h then concentrated in vacuo to leave a crude oil. The oil was crystallized [methanol-dichloromethane (4:1)] to give a purple solid (4.5 g). The solid was dissolved in methanol/tetrahydrofuran (1:1; 30 mL) and Raney Nickel.(R). (1 g) was added. The mixture was cooled to 0° C. and hydrazine hydrate (0.8 mL, 16 mmol) was added in one portion. The mixture was stirred at 0° C. for 90 min then a further aliquot of hydrazine hydrate (0.8 mL) was added. The mixture was stirred at 0° C. for 30 min then filtered through celite.(R). and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated in vacuo and purified by column chromatography [SiO₂; heptane-dichloromethane (4:1)] to give the product (1.7 g, 16percent) as an off-white solid: IR ν_max (nujol)/cm^-1 3395, 2925, 2855, 1570, 1469, 1451, 1408, 1314, 1145, 1105, 865, 763 and 502; NMR δ_H (400 MHz, CDCl₃) 7.85 (1H, br. s), 7.55 (1H, d, J 5.5 Hz), 7.34 (1H, d, J 9 Hz), 7.23 (1H, t, J 2.8 Hz), 6.49-6.51 (1H, m).

Reference： [1] Patent: US6380238, 2002, B1,

3
[ 224185-19-7 ]
[ 259860-08-7 ]

Reference： [1] Patent: WO2018/13867, 2018, A1,

4
[ 259860-00-9 ]
[ 259860-08-7 ]

Reference： [1] Patent: US6380238, 2002, B1,

[ 259860-08-7 ] Synthesis Path-Downstream 1~64

1
[ 259860-08-7 ]
[ 30354-18-8 ]
[ 791066-12-1 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at 20℃;	To a solution of <strong>[259860-08-7]6-bromo-5-fluoro-1H-indole</strong> (0.86 g, 4.02 mmol) in CH2Cl2 (30 ml) was added N,N-dimethyl methyleneiminium chloride (0.5 g, 5.34 mmol). The mixture was stirred at room temperature overnight and a aqueous sodium hydroxide (0.22 g, 5.50 mmol, 100 ml water) was added. The aqueous solution was extracted into ethyl acetate. The organic extract was dried (anhydrous sodium sulfate) and concentrated under reduced pressure to give (6-Bromo-5-fluoro-1H-indol-3-ylmethyl)-dimethyl-amine as a light green solid (1.06 g). 1H NMR (DMSO) d: 2.12 (s, 6H), 3.48 (s, 2H), 7.34 (s, 1H), 7.50(d, 1H, J=9.9 Hz), 7.62 (d, 1H, J=6.0 Hz). M-H: 269.

Reference： [1]Patent: US2004/224973,2004,A1 .Location in patent: Page 22

2
[ 1034894-73-9 ]
[ 259860-08-7 ]

Yield	Reaction Conditions	Operation in experiment
89%	With iron; acetic acid; In ethanol; at 90℃;	The enamine (1.89 g, 4.38 mmol) was dissolved in EtOH (35.0 ml_). To this solution Fe (4.42 g, 79.0 mmol) and acetic acid (35.0 ml_) were added and the mixture was stirred at 90 C for overnight. The resulting mixture was filtered and concentrated. The residue was purified by column chromatography (ethyl acetate-hexane; 1 :9) to afford 6- bromo-5-fluoro-1 H-indole as a yellow solid (0.83 g, 89%). 1H NMR (CDCI3, 400 MHz): 6.52 (m, 1 H), 7.27 (m, 1 H), 7.38 (d, J = 9.3 Hz, 1 H), 7.57 (d, J = 5.7 Hz, 1 H), 8.18 (br. s, 1 H).
61%	With hydrazine;nickel; In tetrahydrofuran; methanol; at 20℃;	Synthesis of 6-Bromo-5-fluoroindole was carried out in this step according to the procedure reported by A. D. Batcho and W. Leimgruber; Org. Synth. 1985, 63, 214. A mixture of hydrazine hydrate (1.30 ml, 26.8 mmoles), crude [2-(4-Bromo-5-fluoro-2-nitro-phenyl)-vinyl]-dimethyl-amine as from step 2 and Raney nickle in tetrahydrofuran (30 ml) and methanol (30 ml) was stirred at room temperature over night. The catalyst was removed by filtration through celite and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 0.1N hydrogen chloride solution. The organic extract was washed with brine, dried (anhydrous sodium sulfate), and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluding with 10% ethyl acetate in hexane to give 6-Bromo-5-fluoro-1H-indole as a light green solid (0.865 g, 61%). 1H NMR (CDCl3) d: 6.49-6.51 (m, 1H), 7.23-7.26 (m, 1H), 7.36 (d, 1H, J=9.2 Hz), 7.56 (dd, 1H, J=5.6 Hz, 0.9 Hz), 8.14 (bs, 1H).

Reference： [1]Patent: WO2008/77138,2008,A1 .Location in patent: Page/Page column 77
[2]Patent: US2004/224973,2004,A1 .Location in patent: Page 22

3
aluminum nickel [ No CAS ]
[ 4637-24-5 ]
[ 224185-19-7 ]
[ 259860-08-7 ]

Yield	Reaction Conditions	Operation in experiment
16%	With hydrazine hydrate; In tetrahydrofuran; methanol; N,N-dimethyl-formamide;	6-Bromo-5-fluoroindole N,N-Dimethylformamide dimethylacetal (8.5 mL, 60 mmol) was added in one portion to a stirred solution of 3-bromo-4-fluoro-6-methylnitrobenzene (11.8 g, 50 mmol) in N,N-dimethylformamide (30 mL) at room temperature under Ar. The mixture was heated to 120 C., stirred for 16 h then concentrated in vacuo to leave a crude oil. The oil was crystallized [methanol-dichloromethane (4:1)] to give a purple solid (4.5 g). The solid was dissolved in methanol/tetrahydrofuran (1:1; 30 mL) and Raney Nickel (1 g) was added. The mixture was cooled to 0 C. and hydrazine hydrate (0.8 mL, 16 mmol) was added in one portion. The mixture was stirred at 0 C. for 90 min then a further aliquot of hydrazine hydrate (0.8 mL) was added. The mixture was stirred at 0 C. for 30 min then filtered through celite and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated in vacuo and purified by column chromatography [SiO2; heptane-dichloromethane (4:1)] to give the product (1.7 g, 16%) as an off-white solid: IR numax (nujol)/cm-1 3395, 2925, 2855, 1570, 1469, 1451, 1408, 1314, 1145, 1105, 865, 763 and 502; NMR deltaH (400 MHz, CDCl3) 7.85 (1H, br. s), 7.55 (1H, d, J 5.5 Hz), 7.34 (1H, d, J 9 Hz), 7.23 (1H, t, J 2.8 Hz), 6.49-6.51 (1H, m).

Reference： [1]Patent: US6380238,2002,B1

4
[ 259860-08-7 ]
[ 74-88-4 ]
[ 1034894-76-2 ]

Yield	Reaction Conditions	Operation in experiment
99%		To the solution of 6- bromo-5-fluoro-1 H-indole (0.92g, 4.28 mmol) in dry DMF (10 ml_) was added sodium hydride as 60% in oil (0.26 g, 6.41 mmol) at 0 C. The mixture was stirred at 0 C for 30 min, and then iodomethane (0.32 ml_, 5.14 mmol) was added. The mixture was stirred for 1 hour at room temperature, and then quenched with ice and extracted with EtOAc (50 ml_). The organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (EtOAc-hexane, 1 :9) give 6- bromo-5-fluoro-1 -methyl-1 H-indole as a colorless solid (0.97 g, 99%). 1H NMR (CDCI3, 400 MHz): 3.66 (s, 3H), 6.43 (d, J = 2.7 Hz, 1 H), 7.05 (d, J = 2.7 Hz, 1 H), 7.34 (d, J = 9.3 Hz, 1 H), 7.44 (d, J = 5.4 Hz, 1 H).

Reference： [1]Patent: WO2008/77138,2008,A1 .Location in patent: Page/Page column 77

5
[ 259860-08-7 ]
[ 98-80-6 ]
[ 1403898-90-7 ]

Reference： [1]Patent: WO2012/143726,2012,A1

6
[ 259860-08-7 ]
[ 98-80-6 ]
[ 1403898-91-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 85℃; for 18h;Inert atmosphere;	Preparation 36: 5-Fluoro-6-phenyl-2,3-dihydro-1 H-indoleA mixture of 6-bromo-5-fluoro-1 H-indole (0.214 g, 1 mmol), phenylboronic acid (0.171 g, 1 .4 mmol), sodium carbonate (1 .06 g, 10 mmol), Pd(PPh3)4 (0.1 16 g, 0.1 mmol), 1 ,2- dimethoxyethane (5 mL) and water (5 mL) was stirred under nitrogen at 85 C for 18 h. The mixture was partitioned between water (20 mL) and DCM (2 x 30 mL) and the combined extracts were dried (Na2S04) and evaporated in vacuo to give an oil. Chromatography (Si02; gradient elution with 0 - 50% Et20 in petrol) gave 5-fluoro-6-phenyl-1 H-indole (0.202 g, 95%) as a pale green solid. MS: [M+H]+ = 212. A solution of borane in THF (1 M, 1 .42 mL) was added to 5-fluoro-6-phenyl-1 H-indole (0.20 g, 0.95 mmol) under nitrogen with external cooling using an ice-MeOH bath. The resulting mixture was stirred at 0 C for 0.5 h, then TFA was added dropwise over 0.1 h. The mixture was stirred at 0 C for 1 h then a solution of sodium hydroxide (0.8 g, 20 mmol) and water (5 mL) was added dropwise over 0.1 h. The resulting mixture was partitioned between water (20 mL) and DCM (2 x 30 mL) and the combined organic extracts were dried (Na2S04) and evaporated in vacuo to give an oil. Chromatography (Si02; gradient elution with 0 - 100% Et20 in petrol) gave the title compound (0.17 g, 85%) as an oil. MS: [M+H]+ = 214.
92%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; ethanol; at 20℃;Inert atmosphere; Reflux;	To a suspension of tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4, 0.54 g, 0.467 mmol] in 20 mL of ethylene glycol dimethyl ether (DME) was added <strong>[259860-08-7]6-bromo-5-fluoroindole</strong> (1.00 g, 4.67 mmol), and the mixture was stirred for 15 minutes under argon at room temperature. A solution of phenylboronic acid (0.57 g, 4.67 mmol) in 2-3 mL of ethanol was added and the mixture was stirred for 10 minutes under the same conditions. A solution of potassium carbonate (0.97 g, 7.01 mmol) in 2 mL of water was added to above mixture and the resulting reaction mixture was heated at reflux for 3-4 hours under the argon atmosphere. After the end of the reaction was established by TLC, the reaction was diluted by brine, extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. The product was purified by a silica gel column using ethyl acetate and hexanes (1:3) as eluent to afford 0.90 g (92% yield) of the titled compound as light brown solid.+

Reference： [1]Patent: WO2012/143726,2012,A1 .Location in patent: Page/Page column 130
[2]Patent: WO2016/172358,2016,A1 .Location in patent: Paragraph 00409-00410
[3]Journal of Medicinal Chemistry,2019,vol. 62,p. 491 - 511

7
[ 259860-08-7 ]
[ 96-32-2 ]
[ 1415928-95-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 1h;	D77Methyl 2-(6-bromo-5-fluoro-lH-in6-Bromo-5-fluoro-lH-indole (10 g, 46.7 mmol) was dissolved in DMF (100 mL) and cooled to 0 C in an ice bath before the addition of sodium hydride, 60% dispersion in mineral oil (3.74 g, 93 mmol) and methyl 2-bromoacetate (8.59 mL, 93 mmol). The ice bath was removed and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was cooled with an ice bath once again then quenched with water (50 mL). The aqueous layer was extracted with DCM (3 x 200 mL). The organics were combined, passed through a hydrophobic frit and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0- 40% ethyl acetate in cyclohexane to afford the title compound (10.209 g). LCMS (A): m/z (M+H)+ 286/288, CI lH9BrFN02 requires 285/287 (acidic).

Reference： [1]Patent: WO2012/170752,2012,A1 .Location in patent: Page/Page column 63

8
[ 259860-08-7 ]
[ 1415928-96-9 ]

Reference： [1]Patent: WO2012/170752,2012,A1

9
[ 259860-08-7 ]
[ 1415928-97-0 ]

Reference： [1]Patent: WO2012/170752,2012,A1

10
[ 259860-08-7 ]
[ 1534373-20-0 ]
[ 76-05-1 ]
[ 1534373-03-9 ]

Yield	Reaction Conditions	Operation in experiment
89%		a) A microwave vial was charged with 6-bromo-5 -fluoro- lH-indole (0.338 mmol) and PdCl2(dppf)-CH2Cl2 adduct (13.78 mg, 0.017 mmol). To this was added 4-cyclopropyl-9-[2- fluoro-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyl]methyl} - 1 -oxa-4,9- diazaspiro[5.5]undecan-3-one (0.130 mmol) in 1,4-dioxane (2.5 mL) followed by 2M aq. potassium carbonate (0.130 mL). The vessel was flushed with nitrogen, sealed then irradiated in a microwave reactor at 130 C for 20 min. The reaction mixture was filtered, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with IN aq. sodium bicarbonate and brine, dried over sodium sulfate, and evaporated to dryness. The residue was dissolved in DMSO, filtered and purified by reverse phase HPLC (12-42% acetonitrile w/ 0.1% TF A/water w/ 0.1% TFA). The appropriate fractions were combined and lyophilized to afford the title compound (52 mg, 89%). MS(ES)+ m/e 452.0 [M+H]+.

Reference： [1]Patent: WO2014/8223,2014,A2 .Location in patent: Page/Page column 166

11
[ 1189-71-5 ]
[ 259860-08-7 ]
[ 1211593-30-4 ]