[ CAS No. 1232431-11-6 ] {[proInfo.proName]}

Name: 1232431-11-6|5-Bromo-4-methoxypyridin-2-amine|95%
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Quality Control of [ 1232431-11-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1232431-11-6 ]

Product Details of [ 1232431-11-6 ]

CAS No. :	1232431-11-6	MDL No. :	MFCD15143383
Formula :	C₆H₇BrN₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	TWXZYWWOMADXFJ-UHFFFAOYSA-N
M.W :	203.04	Pubchem ID :	53485433
Synonyms :

Calculated chemistry of [ 1232431-11-6 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	42.83
TPSA :	48.14 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.71 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.63
Log Po/w (XLOGP3) :	1.17
Log Po/w (WLOGP) :	1.44
Log Po/w (MLOGP) :	0.72
Log Po/w (SILICOS-IT) :	1.31
Consensus Log Po/w :	1.26

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.21
Solubility :	1.24 mg/ml ; 0.00611 mol/l
Class :	Soluble
Log S (Ali) :	-1.78
Solubility :	3.4 mg/ml ; 0.0167 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.65
Solubility :	0.453 mg/ml ; 0.00223 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.87

Safety of [ 1232431-11-6 ]

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 [ 1232431-11-6 ]

* 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 [ 1232431-11-6 ]
Downstream synthetic route of [ 1232431-11-6 ]

[ 1232431-11-6 ] Synthesis Path-Upstream 1~1

1
[ 10201-73-7 ]
[ 1232431-11-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-Bromosuccinimide In acetonitrile at 0 - 20℃; for 1 h;	Step 3: 5-bromo-4-methoxyl-2-aminopyridine To a solution of 4-methoxyl-2-aminopyridine (12.4 g, 100 mmol) in acetonitrile (500 mL), N-bromobutanimide (17.8 g, 100 mmol) was added in portions at 0°C under stirring. Upon completion of the addition, the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and CH₂Cl₂ was added. The solution was washed with saturated sodium bicarbonate, dried, and concentrated to give 5-bromo-4-methoxyl-2-aminopyridine (20.3 g, 100percent yield), which was directly used in the next step. MS m/z [ESI]: 203.0 [M+1].
81%	With dihydrogen peroxide; 1-butylpyridinium bromide; toluene-4-sulfonic acid In 1,2-dimethoxyethane at 80℃; for 24 h; Schlenk technique; Inert atmosphere; Green chemistry	General procedure: To a mixture of 2-aminopyridine (0.5 mmol, 1 equiv), p-TSA (0.4 mmol,0.8 equiv), 1-butylpyridinium bromide (1.5 mmol, 3 equiv) in a 50 mL Schlenk tube were added 1,2-dimethoxyethane (2 mL) under air. Then H₂O₂(1.2 mmol, 2.4 equiv) was added. The mixture was stirred at 80°C for 24 h. And then the mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the products.
79%	at 23℃; for 1 h;	Step 1: [0430] To a solution of 4-methoxy-pyridin-2-ylamine (10.0 g, 80.64 mmol) in acetic acid (320 mL) was added Br₂(3.75 mL, 72.58 mmol) in acetic acid (80 mL) dropwise at RT and the resulting RM was stirred at RT for 1 h. The solid precipitate was separated by filtration, washed with hexane and dried to yield 5-bromo-4-methoxy-pyridin-2-ylamine (13.0 g, 79percent). [0431] LC-MS (Method 4): m/z [M+1]⁺=203.1 & 204.8 (MW calc. 203.04); R_t=2.43 min.

73%	With bromine In acetic acid at 0 - 30℃; for 4 h;	2-Amino-4-methoxypyridine (1.24 g, 10 mmol) was dissolved in 100 mL of acetic acid, After cooling to 0 degrees, A solution of bromine (1.92 g, 12 mmol) in acetic acid (30 mL) was added dropwise. Dropping is completed, The solution is reacted at 30 degrees. 4h, TLC monitoring raw material has been completely reacted, To the reaction solution was added 40 mL of saturated aqueous sodium sulfite solution, 25 degrees stirring reaction 0.5h, Concentrated under reduced pressure, The residue was extracted with ethyl acetate (150 mL × 3) Dried over anhydrous sodium sulfate, filter, The filtrate was concentrated under reduced pressure, Column chromatography (V (methylene chloride) / V (methanol) = 20/1), Obtained as a light yellow solid (1.45 g, 73percent).
69%	With bromine In acetic acid at 20℃; for 1 h;	A solution of Br₂ (1 M in AcOH, 10 mL, 10 mmol) was slowly added into a solution commercially available compound 12-1 (1.24 g, 10 mmol) in AcOH (35 mL) at rt. After stirring at rt for 1 hr, the reaction mixture was filtered and the solid was dried in vacuo to give compound 12-2 (1.41 g, 69percent yield). NMR (300 MHz, CD₃OD): δ 7.84 (s, 1 H), 6.29 (s, 1 H), 3.87 (s, 3H) ppm.
47%	With N-Bromosuccinimide; acetic acid In acetonitrile at 20℃; for 1 h; Inert atmosphere	(41c). A mixture of 2-amino-4-methoxypyridine (2.4 g, 19 mol)and N-bromosuccinimide (3.1 g, 17 mmol) was dissolved in aceticacid (6 mL) and stirred at room temperature for 1 h. The reactionmixture was concentrated under vacuum, basified with saturatedaqueous K2CO3 and extracted with EtOAc. The combined organicswere dried, concentrated under vacuum, and purified by silicagel column chromatography, eluting with 50:1 CH2Cl2:MeOH, togive 41c (1.85 g, 47percent). LCMS 203 [M+H]+.
15.1 g	at 20℃; for 1.5 h;	To a stirred solution of 4-methoxypyridin-2-ylamine (15 g, 121 mmol) in acetic acid (490 mL), at room temperature, is slowly added bromine as a 1M solution in acetic acid (120 mL, 120 mmol). After 1.5 h, the reaction mixture is filtered and the collected solid is dissolved in EtOAc. The mixture is washed with saturated NaHCO₃followed by water and then brine. The organic layer is dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure to provide 15.1 g of 5-bromo-4-methoxypyridin-2-ylamine (I-24-1).

Reference： [1] Patent: EP2952510, 2015, A1, . Location in patent: Paragraph 0143
[2] Tetrahedron Letters, 2014, vol. 55, # 36, p. 5058 - 5061
[3] Patent: US2015/166505, 2015, A1, . Location in patent: Paragraph 0428; 0429; 0450
[4] Patent: CN104513257, 2017, B, . Location in patent: Paragraph 0411; 0412; 0413
[5] Patent: WO2012/58125, 2012, A1, . Location in patent: Page/Page column 139; 140
[6] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 15, p. 3947 - 3963
[7] Patent: EP3235816, 2017, A1, . Location in patent: Paragraph 0102-0103
[8] Patent: US2018/72717, 2018, A1, . Location in patent: Paragraph 0283; 0334; 0468

[ 1232431-11-6 ] Synthesis Path-Downstream 1~88

1
[ 10201-73-7 ]
[ 1232431-11-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃; for 1h;	Step 3: 5-bromo-4-methoxyl-2-aminopyridine To a solution of 4-methoxyl-2-aminopyridine (12.4 g, 100 mmol) in acetonitrile (500 mL), N-bromobutanimide (17.8 g, 100 mmol) was added in portions at 0C under stirring. Upon completion of the addition, the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and CH2Cl2 was added. The solution was washed with saturated sodium bicarbonate, dried, and concentrated to give 5-bromo-4-methoxyl-2-aminopyridine (20.3 g, 100% yield), which was directly used in the next step. MS m/z [ESI]: 203.0 [M+1].
81%	With dihydrogen peroxide; 1-butylpyridinium bromide; toluene-4-sulfonic acid; In 1,2-dimethoxyethane; at 80℃; for 24h;Schlenk technique; Inert atmosphere; Green chemistry;	General procedure: To a mixture of 2-aminopyridine (0.5 mmol, 1 equiv), p-TSA (0.4 mmol,0.8 equiv), 1-butylpyridinium bromide (1.5 mmol, 3 equiv) in a 50 mL Schlenk tube were added 1,2-dimethoxyethane (2 mL) under air. Then H2O2 (1.2 mmol, 2.4 equiv) was added. The mixture was stirred at 80C for 24 h. And then the mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the products.
79%	With bromine; acetic acid; at 23℃; for 1h;	Step 1: [0430] To a solution of 4-methoxy-pyridin-2-ylamine (10.0 g, 80.64 mmol) in acetic acid (320 mL) was added Br2 (3.75 mL, 72.58 mmol) in acetic acid (80 mL) dropwise at RT and the resulting RM was stirred at RT for 1 h. The solid precipitate was separated by filtration, washed with hexane and dried to yield 5-bromo-4-methoxy-pyridin-2-ylamine (13.0 g, 79%). [0431] LC-MS (Method 4): m/z [M+1]+=203.1 & 204.8 (MW calc. 203.04); Rt=2.43 min.

73%	With bromine; In acetic acid; at 0 - 30℃; for 4h;	2-Amino-4-methoxypyridine (1.24 g, 10 mmol) was dissolved in 100 mL of acetic acid, After cooling to 0 degrees, A solution of bromine (1.92 g, 12 mmol) in acetic acid (30 mL) was added dropwise. Dropping is completed, The solution is reacted at 30 degrees. 4h, TLC monitoring raw material has been completely reacted, To the reaction solution was added 40 mL of saturated aqueous sodium sulfite solution, 25 degrees stirring reaction 0.5h, Concentrated under reduced pressure, The residue was extracted with ethyl acetate (150 mL × 3) Dried over anhydrous sodium sulfate, filter, The filtrate was concentrated under reduced pressure, Column chromatography (V (methylene chloride) / V (methanol) = 20/1), Obtained as a light yellow solid (1.45 g, 73%).
69%	With bromine; In acetic acid; at 20℃; for 1h;	A solution of Br2 (1 M in AcOH, 10 mL, 10 mmol) was slowly added into a solution commercially available compound 12-1 (1.24 g, 10 mmol) in AcOH (35 mL) at rt. After stirring at rt for 1 hr, the reaction mixture was filtered and the solid was dried in vacuo to give compound 12-2 (1.41 g, 69% yield). NMR (300 MHz, CD3OD): delta 7.84 (s, 1 H), 6.29 (s, 1 H), 3.87 (s, 3H) ppm.
47%	With N-Bromosuccinimide; acetic acid; In acetonitrile; at 20℃; for 1h;Inert atmosphere;	(41c). A mixture of 2-amino-4-methoxypyridine (2.4 g, 19 mol)and N-bromosuccinimide (3.1 g, 17 mmol) was dissolved in aceticacid (6 mL) and stirred at room temperature for 1 h. The reactionmixture was concentrated under vacuum, basified with saturatedaqueous K2CO3 and extracted with EtOAc. The combined organicswere dried, concentrated under vacuum, and purified by silicagel column chromatography, eluting with 50:1 CH2Cl2:MeOH, togive 41c (1.85 g, 47%). LCMS 203 [M+H]+.
41%	With bromine;	5-bromo-4-methoxypyridin-2-amine was prepared from 4-methoxypyridin-2-amine and bromine using Method 25. The product was purified by flash chromatography eluting with EtOAc in hexane (30 % to 70 % gradient) to yield 5-bromo-4-methoxypyridin-2-amine as a white solid (3.15 g, 41 %). MS: m/z = 203.0 [M+H]+.
	With bromine; acetic acid; at 20℃; for 1h;	A solution of compound 7a-1 (500 mg, 4 mmol) in 10 ml of acetic acid was added to a solution of bromine (4 ml, 1 M in acetic acid) and stirred at room temperature for 1 hour. The reaction was complete and the mixture was filtered and extracted with ethyl acetate and saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, separated and concentrated under reduced pressure to give the crude product which was purified by Combi-flash column chromatography to give the compound 7a-2 (340 mg). Purity: 78%, yield: 41%. spectrum data: MS m/z(ESI): 203[M+H]+.
15.1 g	With bromine; acetic acid; at 20℃; for 1.5h;	To a stirred solution of 4-methoxypyridin-2-ylamine (15 g, 121 mmol) in acetic acid (490 mL), at room temperature, is slowly added bromine as a 1M solution in acetic acid (120 mL, 120 mmol). After 1.5 h, the reaction mixture is filtered and the collected solid is dissolved in EtOAc. The mixture is washed with saturated NaHCO3 followed by water and then brine. The organic layer is dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure to provide 15.1 g of 5-bromo-4-methoxypyridin-2-ylamine (I-24-1).

Reference： [1]Patent: EP2952510,2015,A1 .Location in patent: Paragraph 0143
[2]Tetrahedron Letters,2014,vol. 55,p. 5058 - 5061
[3]Patent: US2015/166505,2015,A1 .Location in patent: Paragraph 0428; 0429; 0450
[4]Patent: CN104513257,2017,B .Location in patent: Paragraph 0411; 0412; 0413
[5]Patent: WO2012/58125,2012,A1 .Location in patent: Page/Page column 139; 140
[6]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3947 - 3963
[7]Patent: WO2019/79373,2019,A1 .Location in patent: Paragraph 00262
[8]Patent: EP3235816,2017,A1 .Location in patent: Paragraph 0102-0103
[9]Patent: US2018/72717,2018,A1 .Location in patent: Paragraph 0283; 0334; 0468

2
[ 291519-97-6 ]
[ 1232431-11-6 ]
[ 1374233-54-1 ]

Yield	Reaction Conditions	Operation in experiment
65%		A mixture of compound 12-2 (1.41 g, 6.9 mmol) and 2-bromo-3-(4-fluoro- phenyl)-3-oxo-propionic acid ethyl ester (12-3) (1.01 g, 3.5 mmol) in ethanol (100 mL) was stirred at 70 C for 22 hrs. The solvent was removed and the residue was partitioned between DCM (50 mL) and water (25 mL). The organic layer was washed with sat. aq. Na2C03 solution and water and dried with anhydrous Na2S04. The solvent was removed and the residue was purified by silica gel column chromatography (EtOAc/DCM = 1/10 (v/v)) to give compound 12-4 (0.90 g, 65% yield). lH NMR (300 MHz, CDC13): delta 9.57 (s, 1H), 7.74 - 7.78 (m, 2H), 7.09 - 7.15 (m, 2H), 7.04 (s, 1H), 4.31 (q, J = 7.2 Hz, 2H), 4.00 (s, 3H), 1.25 (t, / = 7.2 Hz, 3H) ppm.

Reference： [1]Patent: WO2012/58125,2012,A1 .Location in patent: Page/Page column 139; 140

3
[ 1232431-11-6 ]
[ 1374233-55-2 ]

Reference： [1]Patent: WO2012/58125,2012,A1

4
[ 1232431-11-6 ]
[ 1374233-57-4 ]

Reference： [1]Patent: WO2012/58125,2012,A1

5
[ 1232431-11-6 ]
[ 1374233-56-3 ]

Reference： [1]Patent: WO2012/58125,2012,A1

6
[ 1232431-11-6 ]
[ 1374233-58-5 ]

Reference： [1]Patent: WO2012/58125,2012,A1

7
[ 1232431-11-6 ]
[ 1374230-90-6 ]
[ 1374230-84-8 ]

Reference： [1]Patent: WO2012/58125,2012,A1

8
[ 1232431-11-6 ]
[ 1374230-90-6 ]

Reference： [1]Patent: WO2012/58125,2012,A1

9
[ 1232431-11-6 ]
[ 1374229-77-2 ]

Reference： [1]Patent: WO2012/58125,2012,A1

10
[ 1232431-11-6 ]
5-bromo-4-methoxy-2-nitro-pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With sulfuric acid; dihydrogen peroxide; at 0 - 20℃;	At 0 C, to a solution of <strong>[1232431-11-6]5-bromo-4-methoxypyridin-2-amine</strong> (2.98 g, 14.65 mmol) in sulfuric acid (36 mL) was added dropwise a solution of H2O2 (32 mL, 1.30 mol, 30 %) in sulfuric acid (36 mL). The resulting mixture was stirred for 10 min at 0 C, warmed up to room temperature, and stirred for additional 1 h at room temperature. When the reaction was done, the pH value of the reaction mixture was adjusted to 7-8 with sat. sodium carbonate solution. The resulting mixture was extracted with ethyl acetate (500 mL x 3). The organic phases were combined, washed with brine and dried over Na2S04. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0 % to 95 % gradient) to yield 5-bromo-4- methoxy-2-nitropyridine as a white solid (801 mg, 25 %). MS: m/z = 234.6 [M+H]+.
20%	With sulfuric acid; dihydrogen peroxide; at 0 - 23℃; for 3h;	Step 2: [0433] To a mixture of H2O2 (16 mL) and conc. H2SO4 (20 mL) was added dropwise a solution of <strong>[1232431-11-6]5-bromo-4-methoxy-pyridin-2-ylamine</strong> (2.0 g, 9.85 mmol) in conc. H2SO4 (20 mL) at 0 C. and the resulting RM was stirred at RT for 3 h. The RM was neutralized with sat.NaHCO3 solution up to pH7-8 and extracted with EtOAc. The organic layer was dried and concentrated under reduced pressure to give the crude product which was purified by CC (SiO2; 4% EtOAc/Hex) to yield 5-bromo-4-methoxy-2-nitro-pyridine (470 mg, 20%).

Reference： [1]Patent: WO2019/79373,2019,A1 .Location in patent: Paragraph 00262; 00263
[2]Patent: US2015/166505,2015,A1 .Location in patent: Paragraph 0428; 0432; 0433; 0434

11
[ 1232431-11-6 ]
5-bromo-2-cyclopropoxy-4-methoxypyridine [ No CAS ]

Reference： [1]Patent: US2015/166505,2015,A1

12
[ 1232431-11-6 ]
C₁₅H₁₇N₃O₄ [ No CAS ]

Reference： [1]Patent: US2015/166505,2015,A1

13
[ 1232431-11-6 ]
tert-butyl 4-(5-bromo-4-methoxypyridin-2-yl)-5,6-dihydropyridin-1(2H)-carboxylate [ No CAS ]

Reference： [1]Patent: EP2952510,2015,A1

14
[ 1232431-11-6 ]
2,5-dibromo-4-methoxypyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%		Step 4: 2,5-dibromo-4-methoxypyridine 5-Bromo-4-methoxy-2-aminopyridine (20.3 g, 100 mmol) was dissolved in 40% HBr (60 mL) and water (40 mL) at -10C under stirring, and then a solution of NaNO2 (17.3 g, 250 mmol) in water (25 mL) was added. The mixture was stirred at low temperature for 30 minutes. Liquid bromine (48.0 g, 300 mmol) was added, and stirring was continued for 2 hours. Concentrated NaOH was added to adjust the pH value to greater than 12, and then the resultant was extracted by ethyl acetate. The extract was dried, concentrated, and purified by silica gel column chromatography to give 2,5-dibromo-4-methoxypyridine (13.8 g, 52% yield). MS m/z [ESI]: 267.9 [M+1].

Reference： [1]Patent: EP2952510,2015,A1 .Location in patent: Paragraph 0144

15
[ 943937-26-6 ]
[ 1232431-11-6 ]
[ 76-05-1 ]
4-methoxy-5-(1-(3-methoxypropyl)-1,2,3,4-tetrahydroquinolin-7-yl)pyridin-2-amine trifluoroacetic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%		A mixture of 42 (100 mg, 0.3 mmol), 41c (61 mg, 0.3 mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol), andaqueous Na2CO3 solution (2 N, 0.3 mL) in dioxane (5 mL) was stirredat 80 C overnight under argon. The mixture was cooled toroom temperature, filtered, and the filtrate was concentratedunder vacuum. The crude residue was purified by preparative HPLC(column: Phenomenex Gemini 5 lm C18 150 21.2 mm; injectionvolume: 4 mL; flow rate: 20 mL/min; wavelength: 214 nm and254 nm; elution: linear gradient of 25:75 CH3CN:water (0.1% v/vTFA) to 50:50 CH3CN:water (0.1% v/v TFA) over 10 min) to give14 (25 mg, 19%) as the TFA salt as a white solid. 1H NMR(300 MHz, CD3OD) d 7.65 (s, 1H), 6.98 (d, 1H, J = 9.0 Hz), 6.77 (s,1H), 6.64 (d, 1H, J = 9.0 Hz), 3.97 (s, 3H), 3.48-3.34 (m, 6H), 3.32(s, 3H), 2.81-2.77 (m, 2H), 2.03-1.95 (m, 2H), 1.92-1.83 (m, 2H).LCMS 328 [M+H]+.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3947 - 3963

16
[ 1232431-11-6 ]
4-(6-(tert-butylsulfonyl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridin-3-yl)-6-chloropyridin-2-amine [ No CAS ]