[ CAS No. 875781-44-5 ] {[proInfo.proName]}

Name: 875781-44-5|5-Bromo-3-iodo-4,7-diazaindole|95%
Brand: Ambeed
SKU: A157699
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Quality Control of [ 875781-44-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 875781-44-5 ]

SDS Specification

Alternatived Products of [ 875781-44-5 ]

Product Details of [ 875781-44-5 ]

CAS No. :	875781-44-5	MDL No. :	MFCD09878696
Formula :	C₆H₃BrIN₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ULGMTONBTOMHOK-UHFFFAOYSA-N
M.W :	323.92	Pubchem ID :	44118277
Synonyms :

Calculated chemistry of [ 875781-44-5 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	54.31
TPSA :	41.57 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) :	-6.86 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.71
Log Po/w (XLOGP3) :	2.0
Log Po/w (WLOGP) :	2.32
Log Po/w (MLOGP) :	1.44
Log Po/w (SILICOS-IT) :	3.21
Consensus Log Po/w :	2.14

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.71
Solubility :	0.0626 mg/ml ; 0.000193 mol/l
Class :	Soluble
Log S (Ali) :	-2.5
Solubility :	1.03 mg/ml ; 0.00317 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.32
Solubility :	0.0156 mg/ml ; 0.0000482 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.42

Safety of [ 875781-44-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 875781-44-5 ]

* 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 [ 875781-44-5 ]
Downstream synthetic route of [ 875781-44-5 ]

[ 875781-44-5 ] Synthesis Path-Upstream 1~3

1
[ 875781-43-4 ]
[ 875781-44-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 1 h;	Step 1. 2-Bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine. To a solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (8 g, 40.4 mmol) in DMF (160 mL) was added N-iodosuccinimide (11.8 g, 3.6 mmol) at room temperature, and stirred for 1 h. TLC (Petroleum ether: EtOAc, 2:1) indicated the reaction was completed. reaction mixture was diluted with water (500 mL), and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine, and dried over Na₂SO₄. After filtration, the solvent was removed under reduced pressure to give 2-bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine (26.1 g, 100percent) as brown solid (containing some DMF).
95%	With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 2 h; Inert atmosphere	2-bromo-7-iodo-5H-pyrrolof3,2-blpyrazine CIV-E-I); A mixture of III-E-1 (5.0 g, 25 mmol; commercially available from Ark pharma) and freshly ground KOH (5.10 g, 90.9 mmol) in DMF (100 mL) was stirred at RT under N₂ for 30 min. Iodine (6.35 g, 25.02 mmol) was then added in one portion and the red mixture was stirred at RT for 2 h when TLC indicated that the reaction was complete. The mixture was poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried and concentrated to give IV-E-I (7.74 g, 95percent) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ 7.67 (s, IH), 8.23 (s, IH).
89%	With N-iodo-succinimide In acetone at 20℃; for 4 h;	To a solution of 2-bromo-5H-pyrrolo[3,2-Z?]pyrazine [Intermediate AS] (0.68 g, 3.4 mmol) in acetone (17 mL) was added N-iodosuccinimide (0.82 g, 3.6 mmol) and the resulting mixture was stirred for 4 h at rt. The mixture was evaporated in vacuo to yield a residue that was purified via silica gel chromatography eluting with 40percent TΗF in hexanes to give the title compound as a yellow solid (0.99 g, 89percent). ¹H ΝMR (DMSO-J6, 300 MHz): δ 12.82 (s, IH), 8.42 (s, 1 H), 8.20 (s, 1 H). HPLC retention time: 2.23 minutes. MS ESI (m/z): 324.0, 326.0 (M+H)⁺, calc. 323.

89%	With N-iodo-succinimide In acetone at 20℃; for 4 h;	Preparation of 2-bromo-7-iodo-5H-pyrr lo [3,2-6] yrazine (Intermediate AT)[0316] To a solution of 2-bromo-5H-pyrrolo[3,2-.pound.]pyrazine [Intermediate AS] (0.68 g, 3.4 mmol) in acetone (17 mL) was added N-iodosuccinimide (0.82 g, 3.6 mmol) and the resulting mixture was stirred for 4 h at rt. The mixture was evaporated in vacuo to yield a residue that was purified via silica gel chromatography eluting with 40percent THF in hexanes to give the title compound as a yellow solid (0.99 g, 89percent). 1H NMR (DMSO-dtf, 300 MHz): δ 12.82 (s, 1H), 8.42 (s, 1 H), 8.20 (s, 1 H). HPLC retention time: 2.23 minutes. MS ESI (m/z): 324.0, 326.0 (M+H)⁺, calc. 323.
89%	With N-iodo-succinimide In acetone at 20℃; for 4 h;	To a solution of 2-bromo-5H-pyrrolo[3,2-Z?]pyrazine (0.68 g, 3.4 mmol) in acetone (17 mL) was added N-iodosuccinimide (0.82 g, 3.6 mmol) and the resulting mixture was stirred for 4 h at rt. The mixture was evaporated in vacuo to yield a residue that was purified via silica gel chromatography eluting with 40percent THF in hexanes to give the title compound as a yellow solid (0.99 g, 89percent). NMR (DMSO-i , 300 MHz): δ 12.82 (s, 1H), 8.42 (s, 1 H), 8.20 (s, 1 H). HPLC retention time: 2.23 minutes. MS ESI (m/z): 324.0, 326.0 (M+H)⁺, calc. 323.

Reference： [1] Patent: US2015/158864, 2015, A1, . Location in patent: Paragraph 0645
[2] Patent: WO2010/15803, 2010, A1, . Location in patent: Page/Page column 43
[3] Patent: WO2010/68483, 2010, A2, . Location in patent: Page/Page column 68
[4] Patent: WO2011/149950, 2011, A2, . Location in patent: Page/Page column 65; 67
[5] Patent: WO2014/85795, 2014, A1, . Location in patent: Paragraph 0283
[6] Patent: WO2006/15124, 2006, A2, . Location in patent: Page/Page column 103

2
[ 875781-41-2 ]
[ 875781-44-5 ]

Reference： [1] Patent: WO2011/149950, 2011, A2,
[2] Patent: WO2014/85795, 2014, A1,

3
[ 875781-42-3 ]
[ 875781-44-5 ]

Reference： [1] Patent: WO2011/149950, 2011, A2,
[2] Patent: WO2014/85795, 2014, A1,

[ 875781-44-5 ] Synthesis Path-Downstream 1~22

1
[ 875781-43-4 ]
[ 875781-44-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-iodo-succinimide; In N,N-dimethyl-formamide; at 20℃; for 1h;	Step 1. 2-Bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine. To a solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (8 g, 40.4 mmol) in DMF (160 mL) was added N-iodosuccinimide (11.8 g, 3.6 mmol) at room temperature, and stirred for 1 h. TLC (Petroleum ether: EtOAc, 2:1) indicated the reaction was completed. reaction mixture was diluted with water (500 mL), and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine, and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure to give 2-bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine (26.1 g, 100%) as brown solid (containing some DMF).
95%	With iodine; potassium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere;	2-bromo-7-iodo-5H-pyrrolof3,2-blpyrazine CIV-E-I); A mixture of III-E-1 (5.0 g, 25 mmol; commercially available from Ark pharma) and freshly ground KOH (5.10 g, 90.9 mmol) in DMF (100 mL) was stirred at RT under N2 for 30 min. Iodine (6.35 g, 25.02 mmol) was then added in one portion and the red mixture was stirred at RT for 2 h when TLC indicated that the reaction was complete. The mixture was poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried and concentrated to give IV-E-I (7.74 g, 95%) as a brown solid. 1H NMR (400 MHz, CDCl3) delta 7.67 (s, IH), 8.23 (s, IH).
89%	With N-iodo-succinimide; In acetone; at 20℃; for 4h;	To a solution of 2-bromo-5H-pyrrolo[3,2-Z?]pyrazine [Intermediate AS] (0.68 g, 3.4 mmol) in acetone (17 mL) was added N-iodosuccinimide (0.82 g, 3.6 mmol) and the resulting mixture was stirred for 4 h at rt. The mixture was evaporated in vacuo to yield a residue that was purified via silica gel chromatography eluting with 40% TEtaF in hexanes to give the title compound as a yellow solid (0.99 g, 89%). 1H NuMR (DMSO-J6, 300 MHz): delta 12.82 (s, IH), 8.42 (s, 1 H), 8.20 (s, 1 H). HPLC retention time: 2.23 minutes. MS ESI (m/z): 324.0, 326.0 (M+H)+, calc. 323.

89%	With N-iodo-succinimide; In acetone; at 20℃; for 4h;	Preparation of 2-bromo-7-iodo-5H-pyrr lo [3,2-6] yrazine (Intermediate AT)[0316] To a solution of 2-bromo-5H-pyrrolo[3,2-£]pyrazine [Intermediate AS] (0.68 g, 3.4 mmol) in acetone (17 mL) was added N-iodosuccinimide (0.82 g, 3.6 mmol) and the resulting mixture was stirred for 4 h at rt. The mixture was evaporated in vacuo to yield a residue that was purified via silica gel chromatography eluting with 40% THF in hexanes to give the title compound as a yellow solid (0.99 g, 89%). 1H NMR (DMSO-dtf, 300 MHz): delta 12.82 (s, 1H), 8.42 (s, 1 H), 8.20 (s, 1 H). HPLC retention time: 2.23 minutes. MS ESI (m/z): 324.0, 326.0 (M+H)+, calc. 323.
89%	With N-iodo-succinimide; In acetone; at 20℃; for 4h;	To a solution of 2-bromo-5H-pyrrolo[3,2-Z?]pyrazine (0.68 g, 3.4 mmol) in acetone (17 mL) was added N-iodosuccinimide (0.82 g, 3.6 mmol) and the resulting mixture was stirred for 4 h at rt. The mixture was evaporated in vacuo to yield a residue that was purified via silica gel chromatography eluting with 40% THF in hexanes to give the title compound as a yellow solid (0.99 g, 89%). NMR (DMSO-i , 300 MHz): delta 12.82 (s, 1H), 8.42 (s, 1 H), 8.20 (s, 1 H). HPLC retention time: 2.23 minutes. MS ESI (m/z): 324.0, 326.0 (M+H)+, calc. 323.
	With N-iodo-succinimide; In acetone; at 20℃; for 0.75h;	Step 4: Synthesis of 2-Bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine.[0285] To a solution of 2-Bromo-5H-pyrrolo[2,3-b]pyrazine (258 mg, 1.3 mmol) inacetone (5 ml) was added Af-iodosuccinimide (324 mg, 1.44 mmol) in one portion. Thereaction mixture was stirred at room temperature for 45 minutes. The resulting precipitatewas filtered off, washed with a minimal amount of acetone, and dried in vacuum to give thetitle compound as a light brown solid ^-NMR (500 MHz, d6-DMSO) £12.81 (s br, 1H),8.40 (s, 1H), 8.19 (d, 3.0Hz, 1H). MS: m/z 323.8/325.8 [MH+].

Reference： [1]Patent: US2015/158864,2015,A1 .Location in patent: Paragraph 0645
[2]Patent: WO2010/15803,2010,A1 .Location in patent: Page/Page column 43
[3]Patent: WO2010/68483,2010,A2 .Location in patent: Page/Page column 68
[4]Patent: WO2011/149950,2011,A2 .Location in patent: Page/Page column 65; 67
[5]Patent: WO2014/85795,2014,A1 .Location in patent: Paragraph 0283
[6]Journal of Medicinal Chemistry,2019,vol. 62,p. 5810 - 5831
[7]Patent: WO2006/15124,2006,A2 .Location in patent: Page/Page column 103

2
[ 875781-44-5 ]
[ 98-09-9 ]
[ 1206903-84-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide; In dichloromethane; water; at 20℃; for 3h;	2-bromo-7-iodo-5-(phenylsulfonyl)-5H-pyrrolor3,2-blpyrazine (V-E-I); A mixture of (IV-E-I) (7.74 g, 23.9 mmol), PhSO2Cl (6.54 g , 4.73 mL , 37.04 mmol), Bu4NHSO4 (1.217 g , 3.584 mmol) and 50% aqueous NaOH (5 mL, 7.65 g, 95.6 mmol) in CH2Cl2 (100 mL) was stirred vigorously at RT for 3 h. A saturated solution of NaHCO3 (50 mL) was added and the mixture was extracted with CH2Cl2 (4 x 50 mL). The combined organic extracts were dried (MgSO4), concentrated, and the residue was triturated with MeOH (100 mL). The solid was filtered off and dried in vacuo to afford V-E-I (9.34 g, 85%) as yellow solid. 1H NMR (400 MHz, CDCl3) delta 7.49-7.60 (m, 2H), 7.62-7.73 (m, IH), 8.15 (d, J0.51, IH), 8.16-8.21 (m, 2H), 8.44 (d, J0.38, IH). MS (ES) M+ m/e = 464.

Reference： [1]Patent: WO2010/15803,2010,A1 .Location in patent: Page/Page column 44

3
[ 875781-44-5 ]
[ 98-59-9 ]
[ 875781-45-6 ]

Yield	Reaction Conditions	Operation in experiment
94%		To a stirred solution of 2-bromo-7-iodo-5H-pyrrolo[3,2-^]pyrazine [ Intermediate AT] (1.1 g, 3.5 mmol) in anhydrous TEtaF (20 mL) cooled to 00C was added NuaEta [60% dispersion in mineral oil] (0.17 g, 4.3 mmol). The reaction mixture was stirred for 20 min at 00C, after which /?-toluenesulfonyl chloride (0.73 g, 3.8 mmol) in TEtaF (8 mL) was added. The resulting mixture was stirred at rt for 3 hr, after which it was diluted with EtOAc and washed with H2O and brine. The organic layer was separated, dried over Na2SO4, filtered, and evaporated in vacuo to yield a residue that was triturated with hexanes to yield the title compound (1.6 g, 94%) as a light yellow powder. 1H NMR (DMSO- d6, 300MHz) delta 8.62 (d, J = 7.5 Hz, 2 H), 8.03 (s, 1 H), 8.00 (s, IH), 7.47 (d, / = 8.1 Hz, 2 H), 2.37 (s, 3H). HPLC retention time: 2.84 minutes. MS ESI (m/z): 478.0/480.0 (M+H)+, calc. 477.
94%		Preparation of 2-bromo-7-iodo-5-tosyl-5H-pyrrolo [3,2-6] pyrazine (Intermediate AU)[0317] To a stirred solution of 2-bromo-7-iodo-5H-pyrrolo[3,2-¾]pyrazine [ Intermediate AT] (1.1 g, 3.5 mmol) in anhydrous THF (20 mL) cooled to 0C was added NaH [60%> dispersion in mineral oil] (0.17 g, 4.3 mmol). The reaction mixture was stirred for 20 min at 0C, after which /?-toluenesulfonyl chloride (0.73 g, 3.8 mmol) in THF (8 mL) was added. The resulting mixture was stirred at rt for 3 hr, after which it was diluted with EtOAc and washed with H20 and brine. The organic layer was separated, dried over Na2S04, filtered, and evaporated in vacuo to yield a residue that was triturated with hexanes to yield the title compound (1.6 g, 94%) as a light yellow powder. 1H NMR (DMSO-dtf, 300MHz) delta 8.62 (d, J= 7.5 Hz, 2 H), 8.03 (s, 1 H), 8.00 (s, 1H), 7.47 (d, J= 8.1 Hz, 2 H), 2.37 (s, 3H). HPLC retention time: 2.84 minutes. MS ESI (m/z): 478.0/480.0 (M+H)+, calc. 477.
94%		To a stirred solution of 2-bromo-7-iodo-5H-pyrrolo[3,2-Z?]pyrazine (1.1 g, 3.5 mmol) in anhydrous THF (20 mL) cooled to 0C was added NaH [60% dispersion in mineral oil] (0.17 g, 4.3 mmol). The reaction mixture was stirred for 20 min at 0C, after which -toluenesulfonyl chloride (0.73 g, 3.8 mmol) in THF (8 mL) was added. The resulting mixture was stirred at rt for 3 hr, after which it was diluted with EtOAc and washed with H 0 and brine. The organic layer was separated, dried over Na2S04, filtered, and evaporated in vacuo to yield a residue that was triturated with hexanes to yield the title compound (1.6 g, 94%) as a light yellow powder. NMR (DMSO-i , 300MHz) delta 8.62 (d, J= 7.5 Hz, 2 H), 8.03 (s, 1 H), 8.00 (s, 1H), 7.47 (d, J= 8.1 Hz, 2 H), 2.37 (s, 3H). HPLC retention time: 2.84 minutes. MS ESI (m/z): 478.0/480.0 (M+H)+, calc. 477.

Reference： [1]Patent: WO2010/68483,2010,A2 .Location in patent: Page/Page column 68-69
[2]Patent: WO2011/149950,2011,A2 .Location in patent: Page/Page column 65; 67-68
[3]Patent: WO2014/85795,2014,A1 .Location in patent: Paragraph 0284

4
[ 875781-41-2 ]
[ 875781-44-5 ]

Reference： [1]Patent: WO2011/149950,2011,A2
[2]Patent: WO2014/85795,2014,A1
[3]Journal of Medicinal Chemistry,2019,vol. 62,p. 5810 - 5831

5
[ 875781-42-3 ]
[ 875781-44-5 ]

Reference： [1]Patent: WO2011/149950,2011,A2
[2]Patent: WO2014/85795,2014,A1

6
[ 875781-44-5 ]
[ 1229583-75-8 ]

Reference： [1]Patent: WO2011/149950,2011,A2
[2]Patent: WO2014/85795,2014,A1

7
[ 875781-44-5 ]
[ 1229582-37-9 ]

Reference： [1]Patent: WO2011/149950,2011,A2
[2]Patent: WO2014/85795,2014,A1

8
[ 875781-44-5 ]
C₃₀H₂₆N₄O₅S [ No CAS ]

Reference： [1]Patent: WO2011/149950,2011,A2

9
[ 875781-44-5 ]
[ 76513-69-4 ]
2-bromo-7-iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine [ No CAS ]