[ CAS No. 882521-63-3 ] {[proInfo.proName]}

Name: 882521-63-3|7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine|98%
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SKU: A218977
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Quality Control of [ 882521-63-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 882521-63-3 ]

SDS Specification

Alternatived Products of [ 882521-63-3 ]

Product Details of [ 882521-63-3 ]

CAS No. :	882521-63-3	MDL No. :	MFCD11846606
Formula :	C₆H₅BrN₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DAYYXZOMYRSLBX-UHFFFAOYSA-N
M.W :	213.03	Pubchem ID :	54594025
Synonyms :

Calculated chemistry of [ 882521-63-3 ]

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 :	45.09
TPSA :	56.21 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) :	-6.83 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.59
Log Po/w (XLOGP3) :	1.09
Log Po/w (WLOGP) :	1.08
Log Po/w (MLOGP) :	1.58
Log Po/w (SILICOS-IT) :	0.45
Consensus Log Po/w :	1.16

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.45
Solubility :	0.751 mg/ml ; 0.00352 mol/l
Class :	Soluble
Log S (Ali) :	-1.86
Solubility :	2.92 mg/ml ; 0.0137 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.21
Solubility :	1.3 mg/ml ; 0.00612 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.94

Safety of [ 882521-63-3 ]

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 [ 882521-63-3 ]

* 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 [ 882521-63-3 ]
Downstream synthetic route of [ 882521-63-3 ]

[ 882521-63-3 ] Synthesis Path-Upstream 1~2

1
[ 882521-62-2 ]
[ 882521-63-3 ]

Yield	Reaction Conditions	Operation in experiment
87.4%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In ethanol at 25℃; for 24 h; Reflux	A mixture of hydroxylamine hydrochloride (20.0 g, 288 mmol) and N-ethyldiisopropylamine (30.1 ml, 173 mmol) in ethanol (367 ml) is stirred for a few minutes at room temperature and the mixture is added to l-ethoxycarbonyl-3-(4-bromo-pyridin-2-yl)-thiourea (17.5 g, 57.5 mmol). The resulting mixture is refluxed for 1 day. The solvent is evaporated and 100 ml water is added to the residue. The suspension is stirred for 10 minutes, the solid is collected by filtration, washed with water and dried affording 7-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-amine (10.71 g, 87.4percent) as a light yellow solid. Mp.: 190-2°C. MS: m/z= 213.0, 215.0 (M+H⁺).
86%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 20 - 60℃; for 5 h;	To a stirred suspension/solution of hydroxylamine hydrochloride (375 mg, 5.40 mmol) and diisopropylethylamine (419 mg, 3.24 mmol) in MeOH/EtOH (1 :1 , 2 mL) was added compound 2 as a solid. This mixture was stirred at room temperature for 2 h, giving a pale yellow suspension, followed by a further 3h, at 60⁰C. The reaction mixture was allowed to cool, diluted with CH₂CI₂ (100 mL), which was then washed with water (2x80 mL) and brine (80 mL). This solution was dried (Na₂SO₄) and the solvent removed under reduced pressure to give 7-bromo-[1 ,2,4]triazolo[1 ,5-a]pyridin-2-ylamine (3) LCMS (APCI⁺) 213, 215.
83%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 20℃; Reflux	2.2 7-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (3); To a suspension of hydroxylamine hydrochloride (4.7g, 68mmol) in EtOH/MeOH (1 :1, 16OmL) was added JV,jV-diisopropylethylamine (7.2mL, 41mmol), the mixture was stirred at room temperature (2O⁰C) for Ih. l-(4-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (4.13g, 13.6mmol) was then added and the mixture slowly heated to reflux (Note: bleach scrubber required to quench H₂S evolved). After 2h at reflux the mixture was allowed to cool and filtered to collect the precipitated solid. The collected solid was washed successively with water (10OmL), EtOH/MeOH (1 :1, 10OmL) and diethyl ether (5OmL) then air-dried to afford the title compound as a white solid (2.4g, 83percent). No further purification was required. LCMS (method C), (M+H⁺) 213/215, Rt = 1.48 min. 1H NMR (de-DMSO) δ 8.50 (d, IH), 7.66 (d, IH), 7.03 (dd, IH), 6.15 (brs, 2H).

78.8%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In ethanol at 25℃; for 24 h; Reflux	b) 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine A mixture of hydroxylamine hydrochloride (20.7 g, 298 mmol) and N-ethyldiisopropylamine (23.1 g, 31.2 ml, 179 mmol) in ethanol (380 ml) is stirred for a few minutes at 25° C. The mixture is then added to 1-ethoxycarbonyl-3-(4-bromo-pyridin-2-yl)-thiourea (18.13 g, 59.6 mmol) and the resulting mixture is refluxed for 1 day. The solvent is evaporated to dryness and the residue triturated for 10 minutes with water (100 ml). The solid is collected by filtration, washed with water and dried affording 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (10 g, 78.8percent) as a light yellow solid. mp.: 190-2° C. MS: m/z=212.9, 215.0 (M+H⁺).
59%	With hydroxylamine hydrochloride; diisopropylamine In methanol; ethanol at 20 - 60℃; for 5 h;	10.61 g (152.677 mmol) of hydroxylamine hydrochloride and 11.84 g (91.606 mmol) N,N- diisopropylamine were dissolved in 60 ml methanol/ethanol (v/v = 1 :1). B-6 g (28.273 mmol) of the compound from example 109A was added and the mixture was stirred at room temperature for 2 h and at 60⁰C for 3 h. After cooling, water and ethyl acetate were added, the organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in a rotary evaporator and the residue was dried under high vacuum. We obtained 4.05 g (59percent of theor.) of the target compound at a purity of 87percent according to LC-MS.LC-MS (method 10): R_t = 0.50 min; MS (EIpos): m/z = 213 [M+H]⁺.1H-NMR (400 MHz, DMSO-D₆): δ [ppm] = 6.13 (s, 2H), 7.02 (dd, IH), 7.65 (dd, IH), 8.49 (dd, IH).
4 g	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 60℃; for 3 h;	To a solution of 2-amino-4-bromopyridine (5.0 g, 28.90 mmol) in dichloromethane (120 mL) at 0 °C, was added ethoxycarbonyl-isothiocyanate (3.41 mL, 28.90 mmol) dropwise for 30 min and stirred at room temperature for 12 h. The solvent was evaporated in vacuo to leave a yellow solid which was triturated with hexane, filtered and air dried. The crude was taken to the next step without any further purification. To a suspension of hydroxylamine hydrochloride (3.61 mL, 86.68 mmol) in a mixture of EtOH/MeOH (1:1, 200 mL) was added N,N-diisopropylethylamine (25 mL, 144.50 mmol) and the mixture was stirred at room temperature for 2 h. The compound 1-(6-bromo-pyridin-2-yl)-3-carboethoxythiourea which was isolated in the previous step was then added and the mixture was slowly heated to 60 °C and stirred for 3 h. The reaction mixture was cooled, and the precipitated solid was filtered. The solid was washed with a mixture of EtOH/MeOH (1:1, 25 mL) followed by diethyl ether (15 mL) and air dried to afford the title compound as white solid. Yield: 65percent (4.00 g) (adapted from ³). ¹H NMR (600 MHz, DMSO-d₆) δ 8.49 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H), 7.01 (dd, J = 7.2, 1.8 Hz, 1H), 6.13 (s, 2H). HRMS-ESI (+) m/z calculated for C₆H₆BrN₄, 212.9776 [M+H]+; found: 212.9780

Reference： [1] Patent: WO2012/76430, 2012, A1, . Location in patent: Page/Page column 90
[2] Patent: WO2006/38116, 2006, A2, . Location in patent: Page/Page column 21
[3] Patent: WO2010/7100, 2010, A1, . Location in patent: Page/Page column 40-41
[4] Patent: US2012/142665, 2012, A1, . Location in patent: Page/Page column 17
[5] Patent: WO2010/20363, 2010, A1, . Location in patent: Page/Page column 129
[6] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4613 - 4618
[7] Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 2, p. 257 - 261

2
[ 84249-14-9 ]
[ 882521-63-3 ]

Reference： [1] Patent: US2012/142665, 2012, A1,
[2] Patent: WO2012/76430, 2012, A1,
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4613 - 4618
[4] Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 2, p. 257 - 261

[ 882521-63-3 ] Synthesis Path-Downstream 1~88

1
[ 882521-63-3 ]
[ 109-90-0 ]
[ 882521-64-4 ]

Yield	Reaction Conditions	Operation in experiment
66%	dibutyltin diacetate; In tetrahydrofuran; toluene; at 100℃; for 24h;	7-Bromo-[1 ,2,4]triazolo[1 ,5-a]pyridin-2-ylamine (compound 3, 1.22 g, 5.73 mmol) was dissolved in THF/toluene (1 :1 , 60 mL), then ethyl isocyanate (4.07 g, 57.3 mmol) and a catalytic quantity of dibutyltindiacetate (6 drops) were added to the mixture. The reaction was then heated in a sealed tube at 1000C for 24 h. This mixture was allowed to cool, then the solvents removed under reduced pressure to afford an oily solid, which was triturated with Et2O, giving a solid which was collected by filtration. Further material was isolated by flash chromatography of the resulting filtrate on silica (2% MeOH/CH2CI2 as eluant) to give compound 1-(7-bromo-[1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl)-3-ethyl-urea (4) LCMS (APCI+) 284, 286.

Reference： [1]Patent: WO2006/38116,2006,A2 .Location in patent: Page/Page column 21

2
[ 882521-62-2 ]
[ 882521-63-3 ]

Yield	Reaction Conditions	Operation in experiment
87.4%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In ethanol; at 25℃; for 24h;Reflux;Product distribution / selectivity;	A mixture of hydroxylamine hydrochloride (20.0 g, 288 mmol) and N-ethyldiisopropylamine (30.1 ml, 173 mmol) in ethanol (367 ml) is stirred for a few minutes at room temperature and the mixture is added to l-ethoxycarbonyl-3-(4-bromo-pyridin-2-yl)-thiourea (17.5 g, 57.5 mmol). The resulting mixture is refluxed for 1 day. The solvent is evaporated and 100 ml water is added to the residue. The suspension is stirred for 10 minutes, the solid is collected by filtration, washed with water and dried affording 7-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-amine (10.71 g, 87.4%) as a light yellow solid. Mp.: 190-2C. MS: m/z= 213.0, 215.0 (M+H+).
86%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20 - 60℃; for 5h;	To a stirred suspension/solution of hydroxylamine hydrochloride (375 mg, 5.40 mmol) and diisopropylethylamine (419 mg, 3.24 mmol) in MeOH/EtOH (1 :1 , 2 mL) was added compound 2 as a solid. This mixture was stirred at room temperature for 2 h, giving a pale yellow suspension, followed by a further 3h, at 600C. The reaction mixture was allowed to cool, diluted with CH2CI2 (100 mL), which was then washed with water (2x80 mL) and brine (80 mL). This solution was dried (Na2SO4) and the solvent removed under reduced pressure to give 7-bromo-[1 ,2,4]triazolo[1 ,5-a]pyridin-2-ylamine (3) LCMS (APCI+) 213, 215.
83%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20℃;Reflux;	2.2 7-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (3); To a suspension of hydroxylamine hydrochloride (4.7g, 68mmol) in EtOH/MeOH (1 :1, 16OmL) was added JV,jV-diisopropylethylamine (7.2mL, 41mmol), the mixture was stirred at room temperature (2O0C) for Ih. l-(4-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (4.13g, 13.6mmol) was then added and the mixture slowly heated to reflux (Note: bleach scrubber required to quench H2S evolved). After 2h at reflux the mixture was allowed to cool and filtered to collect the precipitated solid. The collected solid was washed successively with water (10OmL), EtOH/MeOH (1 :1, 10OmL) and diethyl ether (5OmL) then air-dried to afford the title compound as a white solid (2.4g, 83%). No further purification was required. LCMS (method C), (M+H+) 213/215, Rt = 1.48 min. 1H NMR (de-DMSO) delta 8.50 (d, IH), 7.66 (d, IH), 7.03 (dd, IH), 6.15 (brs, 2H).

78.8%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In ethanol; at 25℃; for 24h;Reflux;Product distribution / selectivity;	b) 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine A mixture of hydroxylamine hydrochloride (20.7 g, 298 mmol) and N-ethyldiisopropylamine (23.1 g, 31.2 ml, 179 mmol) in ethanol (380 ml) is stirred for a few minutes at 25 C. The mixture is then added to 1-ethoxycarbonyl-3-(4-bromo-pyridin-2-yl)-thiourea (18.13 g, 59.6 mmol) and the resulting mixture is refluxed for 1 day. The solvent is evaporated to dryness and the residue triturated for 10 minutes with water (100 ml). The solid is collected by filtration, washed with water and dried affording 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (10 g, 78.8%) as a light yellow solid. mp.: 190-2 C. MS: m/z=212.9, 215.0 (M+H+).
59%	With hydroxylamine hydrochloride; diisopropylamine; In methanol; ethanol; at 20 - 60℃; for 5h;	10.61 g (152.677 mmol) of hydroxylamine hydrochloride and 11.84 g (91.606 mmol) N,N- diisopropylamine were dissolved in 60 ml methanol/ethanol (v/v = 1 :1). B-6 g (28.273 mmol) of the compound from example 109A was added and the mixture was stirred at room temperature for 2 h and at 600C for 3 h. After cooling, water and ethyl acetate were added, the organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in a rotary evaporator and the residue was dried under high vacuum. We obtained 4.05 g (59% of theor.) of the target compound at a purity of 87% according to LC-MS.LC-MS (method 10): Rt = 0.50 min; MS (EIpos): m/z = 213 [M+H]+.1H-NMR (400 MHz, DMSO-D6): delta [ppm] = 6.13 (s, 2H), 7.02 (dd, IH), 7.65 (dd, IH), 8.49 (dd, IH).
4 g	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 60℃; for 3h;	To a solution of 2-amino-4-bromopyridine (5.0 g, 28.90 mmol) in dichloromethane (120 mL) at 0 C, was added ethoxycarbonyl-isothiocyanate (3.41 mL, 28.90 mmol) dropwise for 30 min and stirred at room temperature for 12 h. The solvent was evaporated in vacuo to leave a yellow solid which was triturated with hexane, filtered and air dried. The crude was taken to the next step without any further purification. To a suspension of hydroxylamine hydrochloride (3.61 mL, 86.68 mmol) in a mixture of EtOH/MeOH (1:1, 200 mL) was added N,N-diisopropylethylamine (25 mL, 144.50 mmol) and the mixture was stirred at room temperature for 2 h. The compound 1-(6-bromo-pyridin-2-yl)-3-carboethoxythiourea which was isolated in the previous step was then added and the mixture was slowly heated to 60 C and stirred for 3 h. The reaction mixture was cooled, and the precipitated solid was filtered. The solid was washed with a mixture of EtOH/MeOH (1:1, 25 mL) followed by diethyl ether (15 mL) and air dried to afford the title compound as white solid. Yield: 65% (4.00 g) (adapted from 3). 1H NMR (600 MHz, DMSO-d6) delta 8.49 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H), 7.01 (dd, J = 7.2, 1.8 Hz, 1H), 6.13 (s, 2H). HRMS-ESI (+) m/z calculated for C6H6BrN4, 212.9776 [M+H]+; found: 212.9780

Reference： [1]Patent: WO2012/76430,2012,A1 .Location in patent: Page/Page column 90
[2]Patent: WO2006/38116,2006,A2 .Location in patent: Page/Page column 21
[3]Patent: WO2010/7100,2010,A1 .Location in patent: Page/Page column 40-41
[4]Patent: US2012/142665,2012,A1 .Location in patent: Page/Page column 17
[5]Patent: WO2010/20363,2010,A1 .Location in patent: Page/Page column 129
[6]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4613 - 4618
[7]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 257 - 261

3
[ 911111-80-3 ]
[ 882521-63-3 ]
[ 1204519-52-7 ]

Yield	Reaction Conditions	Operation in experiment
		3.2 In situ coupling method; The aryl bromide (lmmol), pinacol-diboron (l.lmmol), potassium acetate (3mmol) and [l,l 'bis(diphenylphosphino)ferrocene] dichloro-palladium (II) complex with DCM (5mol%) in ACN (3 mL) was heated to 1150C for 30min in the microwave. 7-Bromo- [l,2,4]triazolo[l,5-a]pyridin-2-ylamine (3) (0.8mmol), sodium carbonate (2M aq., 3 eq, 1.5mL) and [l,l 'bis(diphenylphosphino)ferrocene] dichloro-palladium (II) complex with DCM (2.5mol%, 20mg) were then added and the reaction heated for a further Ih at 1300C in the microwave. The crude reaction was then either partitioned between water and ethyl acetate, the phases separated and the organic layer washed with brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo or precipitated by addition of water, the precipitate collected by filtration and washed with ethyl acetate and methanol. The crude residues were either purified by flash chromatography or preparative HPLC if required to afford the desired products.The following examples were prepared using the above methodsExample 15-(2-amino- [ 1 ,2,4] triazolo [ 1 ,5-a] pyridin-7-yl)-N-tert-butylpyridine-3-sulfbnamide1H NMR (de-DMSO) delta 9.26 (d, IH), 9.00 (d, IH), 8.71 (d, IH), 8.58 (t, IH), 7.85 - 7.82 (m, 2H), 7.31 (dd, IH), 6.17 (s, 2H), 1.15 (s, 9H). LCMS (method B), (M+H+) 347, Rt = 1.97 min.

Reference： [1]Patent: WO2010/7100,2010,A1 .Location in patent: Page/Page column 41-42

4
[ 882521-63-3 ]
[ 73183-34-3 ]
[ 1210048-24-0 ]

Yield	Reaction Conditions	Operation in experiment
		Under an argon atmosphere, 0.686 g (0.749 mmol) of tris-(dibenzylidene-acetone)-dipalladium(0) and 0.504 g (1.798 mmol) of tricyclohexylphosphine were dissolved in 75 ml dioxane. It was stirred for 30 min at room temperature. Then 3.488 g (13.734 mmol) of 4,4,4'4'5,5,5'5'-octamethyl- 2,2'-bi-l,3,2-dioxaborolan, 2.660 g (12.486 mmol) of the compound from example HOA and 1.838 g (18.729 mmol) potassium acetate were added and the mixture was stirred overnight at 800C. After cooling, dioxane was added to the reaction mixture and it was filtered on Celite. The filtrate was concentrated in a rotary evaporator at reduced pressure and dried under high vacuum. We obtained 9.300 g of the raw product (purity 25% according to GC-MS), which was used in the next experiment without further purification.GC-MS (method 6): R, = 7.54 min; MS (EIpos): m/z = 260 [M]+.

Reference： [1]Patent: WO2010/20363,2010,A1 .Location in patent: Page/Page column 129-130

5
[ 84249-14-9 ]
[ 882521-63-3 ]

Reference： [1]Patent: US2012/142665,2012,A1
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4613 - 4618
[3]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 257 - 261

6
[ 882521-63-3 ]
[ 1380330-10-8 ]