215364-86-6|3-Bromo-2-methoxypyridin-4-amine| Ambeed

Structure of 215364-86-6

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Quality Control of [ 215364-86-6 ] Purity: 98% SDS Specification

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Product Details of [ 215364-86-6 ]

CAS No. :	215364-86-6
Formula :	C₆H₇BrN₂O
M.W :	203.04
SMILES Code :	NC1=C(Br)C(OC)=NC=C1
MDL No. :	MFCD11656225
InChI Key :	FJBMTFANAYFWPT-UHFFFAOYSA-N
Pubchem ID :	45588365

Safety of [ 215364-86-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 215364-86-6 ] Show Less

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 ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	48.14 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.73
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.17
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.44
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.72
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.31
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.27

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.21
Solubility	1.24 mg/ml ; 0.00611 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.78
Solubility	3.4 mg/ml ; 0.0167 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.65
Solubility	0.453 mg/ml ; 0.00223 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.71 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.83

Application In Synthesis of [ 215364-86-6 ]

* 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.

Downstream synthetic route of [ 215364-86-6 ]

[ 215364-86-6 ] Synthesis Path-Downstream 1~35

1
[ 20265-39-8 ]
[ 215364-86-6 ]

Yield	Reaction Conditions	Operation in experiment
96.6%	With N-Bromosuccinimide; In dichloromethane; at 25℃; for 4h;	To a solution of 2-methoxypyridin-4-amine (5.0 g, 40.28 mmol) in DCM (10 mL) was added NBS (7.17 g, 40.28 mmol) at 0C. Then the reaction mixture was stirred at 25C for 4 hrs. The solvent was removed under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc=5/1 to 2/1) to give the title compound (7.9 g, 38.91 mmol, 96.60% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) d = 7.67 (d, J = 5.6 Hz, 1H), 6.26 (d, J = 5.6 Hz, 1H), 3.90 (s, 3H).
92%	With N-Bromosuccinimide; In dichloromethane; at 0 - 30℃; for 0.5h;	Synthesis of 3-bromo-2-methoxypyridin-4-amine (2) To a solution of 2-methoxypyridin-4-amine (1, 20.0 g, 161.2 mmol) in dichloromethane (200 mL) at 0 C., N-bromo succinimide (26.6 g, 161.2 mmol) was added and the reaction mixture was stirred at 30 C. for 30 min. After completion, the mixture was quenched with ice cold water (100 mL) and the reaction mass was extracted with dichloromethane (300 mL). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude was triturated with n-pentane and diethyl ether to afford 3-bromo-2-methoxypyridin-4-amine (2) as yellow solid. Yield: 30.0 g, 92%; MS (ESI) m/z 203.09[M+1]+.
90%	With N-Bromosuccinimide; In dichloromethane; at 5℃; for 0.5h;	A solution of bromosuccimide (2.15 g, 12.083 mmol) in DCM (25 mL) was added dropwise to a solution of 2-methoxy-pyridin-4-ylamine (1.5 g, 12.083 mmol) in DCM (85 mL) maintaining the temperature below 5 C. The reaction was continued for 30 minutes and then concentrated dry. The residue was taken in EA (50 mL) and washed with water (40 mL) and brine (20 mL). Drying over MgSO4, filtering, and solvent removal afforded the crude product that further purified by chromatography over silica gel (gradient of EA in heptane from 0 to 30%) to a pure oil (2.23 g, 90%). 1H NMR (300 MHz, Chloroform-d) δ 3.96 (s, 3H), 4.59 (s, 2H), 6.28 (d, J=5.6 Hz, 1H), 7.72 (d, J=5.6 Hz, 1H). MS m/z 203 (MH+).

89%	With N-Bromosuccinimide; In dichloromethane; at 0 - 20℃; for 2h;	3-bromo-2-methoxypyridin-4-amine (i42): To a stirred solution of 2-methoxypyridin-4-amine (2 g, 16 mmol) in DCM (1 14 mL), NBS (2.87 g, 16 mmol) was slowly added at 0C and the reaction was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC. After completion , the solvent was concentrated under reduced pressure. The crude product was purified by silica gel (100:200 mesh) column chromatography using 15% ethyl acetate in n-hexanes as eluent to afford 3- bromo-2-methoxypyridin-4-amine (i42) (2.9 g, Yield 89%). 1H NMR (400 MHz, Chloroform-d) δ 3.97 (s, 3H), 4.58 (s, 2H), 6.29 (d, J = 5.7 Hz, 1 H), 7.73 (d, J = 5.6 Hz, 1 H). MS (ESI) m/e (M+1 )+: 203
81%	With N-Bromosuccinimide; In acetonitrile; at 20℃; for 1h;Cooling with ice;	2-Methoxy-4-aminopyridine (3.81 g, 27.5 mmol)And NBS (5 g, 28 mmol) were dissolved in 25 ml and 40 ml of acetonitrile, respectively,Then, NBS dissolved in acetonitrile was added dropwise to the reaction solution under ice-cooling,Followed by reaction at room temperature for 1 h.After completion of the reaction, the reaction solvent was removed and extracted with ethyl acetate. After completion of the extraction, the solvent was removed and recrystallized from acetone to give Compound 34a (895 mg, 81%).
77%	With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃;	2-methoxy-4-aminopyridine (5 g, 40.3 mmol) was dissolved in MeCN and NBS (7.18 g, 40.3 mmol) was added therein in portions at 0 C. The mixture was slowly raised to room temperature and was allowed to react with stirring and the reaction was monitored by TLC. After the reaction was completed, the resultant was diluted with EA, washed with saturated NH4Cl solution, sodium hydrosulfite and saturated NaCl, dried over anhydrous Na2SO4 and concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound, yield 77%. 1H NMR (300 MHz, CDCl3) δ 7.57 (d, 1H), 6.36 (d, 1H), 6.20 (s, 2H), 3.7 (s, 3H).
	With N-Bromosuccinimide; In acetonitrile; at 10℃;	The 2-[2-methoxy-4-(7-methoxy-l,6-naphthyridin-4-yloxy)phenyl]acetic acid used as a starting material was prepared as follows :-; A solution of iV-bromosuccinimide (9.8 g) in acetonitrile (80 ml) was added dropwise to a stirred solution of 2-methoxypyridine-4-amine CHeIv. Chim. Acta, 1964, 363-376; 6.82 g) in acetonitrile (40 ml) that had been cooled to 10C. The mixture was concentrated by evaporation. The oily residue was triturated under a mixture of diethyl ether and petroleum ether (b.p. 40-60C). There was thus obtained 3-bromo-2-methoxypyridine-4-amine as a solid (11 g); 1R NMR Spectrum: (DMSOd6) 3.8 (s, 3H), 6.21 (br s, 2H), 6.35 (d, IH), 7.59 (d, IH); Mass Spectrum: M+H4" 203 and 205.

References: [1]Patent: WO2020/144638,2020,A1 .Location in patent: Page/Page column 86.
[2]Patent: US2017/145026,2017,A1 .Location in patent: Paragraph 0719; 0720.
[3]Journal of Medicinal Chemistry,2020,vol. 63,p. 5879 - 5955.
[4]Patent: US2019/381019,2019,A1 .Location in patent: Paragraph 0722-0724.
[5]Patent: WO2016/124508,2016,A1 .Location in patent: Page/Page column 60; 61.
[6]Patent: CN107151240,2017,A .Location in patent: Paragraph 0498; 0499; 0500.
[7]Patent: US2018/244667,2018,A1 .Location in patent: Paragraph 0106.
[8]Tetrahedron,2008,vol. 64,p. 2772 - 2782.
[9]Patent: WO2007/113565,2007,A1 .Location in patent: Page/Page column 98.

2
[ 215364-86-6 ]
[ 15568-85-1 ]
[ 952138-16-8 ]

Yield	Reaction Conditions	Operation in experiment
92%	In isopropyl alcohol; at 110℃; for 3h;	1 eq of 3-bromo-2-methoxy-4-aminopyridine was dissolved in isopropanol, then 2 eq of compound 49 was added thereto. After heating to 110 C., the mixture was allowed to react for 1 h with stirring, and then a large amount of solid was precipitated. 2 h later, the solid was cooled to room temperature, washed with isopropanol and ether to give the product compound 57, yield 92%; The compound obtained above was suspended in diphenyl ether at 10 ml/g, and the mixture was heated to 220 C. and allowed to react for 1 h with stirring, and then a large amount of solid was precipitated, which was cooled to room temperature, washed with a large amount of petroleum ether and filtered to give the compound 58, yield 96%. The above solid was dissolved in methanol, and 2 eq of ammonium formate was added therein followed by the addition of 10 wt % of 10% Pd/C. The mixture was allowed to react with stirring at 60 C. and the reaction was monitored by TLC. After the reaction was completed, the resultant was cooled and filtered, the filtrate was concentrated and then extracted with EA, washed with saturated NaCl, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the compound 59. 1H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 8.46 (s, 1H), 7.87 (d, J=7.6 Hz, 1H), 6.75 (s, 1H), 5.97 (d, J=7.6 Hz, 1H), 3.91 (s, 3H).
	In isopropyl alcohol; at 20 - 75℃; for 0.75h;	5-(Methoxymethylidene)-2,2-dimethyl-l,3-dioxane-456-dione (12.1 g) was added to a suspension of 3-bromo-2-methoxypyridine-4-amine (17 g) in isopropanol (160 ml) at ambient temperature. The resultant mixture was stirred and heated to 75C for 45 minutes. The mixture was cooled to ambient temperature and diluted with diethyl ether. The precipitate was5 isolated. There was thus obtained 5-[(3-bromo-2-methoxypyridin-4-ylamino)methylidene]- 2,2-dimethyl-l,3-dioxane-4,6-dione (17 g); 1H NMR Spectrum: (DMSOd6) 1.71 (s, 6H), 3.96 (s, 3H), 7.57 (d, IH), 8.15 (d, IH)5 8.86 (d, IH), 11.58 (br d, IH); Mass Spectrum: M+H+ 357 and 359.

References: [1]Tetrahedron,2008,vol. 64,p. 2772 - 2782.
[2]Patent: US2018/244667,2018,A1 .Location in patent: Paragraph 0107-0109.
[3]Patent: WO2007/113565,2007,A1 .Location in patent: Page/Page column 99.

3
[ 67-56-1 ]
[ 215364-85-5 ]
[ 215364-86-6 ]

Yield	Reaction Conditions	Operation in experiment
		Methanol (350 mL) was charged in a two-neck round bottom flask equipped with a guard tube and septum and cooled to 0 0C. Sodium metal (23 g) was added to it slowly in pieces. After all sodium metal had dissolved, 4-amino-3-bromo-2-chloro pyridine (23 g, 178 mmol) was added and the solution was heated at 180 0C in a pressure vessel for 5-6 h. The reaction mixture was then cooled to 0 0C and adjusted to pH 8 by addition of cone. HCl. Solvent was removed under reduced pressure and the residue was suspended in ethyl acetate, ndissolved impurities were removed by filtration and the filtrate was concentrated under reduced pressure to obtain pure product .
		Step 2: 4-amino-3-bromo-2-methoxypyridine Methanol (350 mL) was charged in a two-neck RBF equipped with a guard tube and septum and cooled to 0 C. Sodium metal (23 g) was added to it slowly in pieces. After all sodium metal had dissolved, 4-amino-3-bromo-2-chloro pyridine (23 g, 178 mmol) was added and the solution was heated at 180 C. in a pressure vessel for 5-6 h. The reaction mixture was then cooled to 0 C. and adjusted to pH 8 by addition of conc. HCl. Solvent was removed under reduced pressure and the residue was suspended in ethyl acetate. Undissolved impurities were removed by filtration and the filtrate was concentrated under reduced pressure to obtain pure product.
		Step 2: 4-amino-3-bromo-2-methoxypyridine; Methanol (350 mL) was charged in a two- neck RBF equipped with a guard tube and septum and cooled to 0 0C. Sodium metal (23 g) was added to it slowly in pieces. After all sodium metal had dissolved, 4-amino-3- bromo-2-chloro pyridine (23 g, 178 mmol) was added and the solution was heated at 180 0C in a pressure vessel for 5-6 h. The reaction mixture was then cooled to 0 0C and adjusted to pH 8 by addition of cone. HCl. Solvent was removed under reduced pressure and the residue was suspended in ethyl acetate. Undissolved impurities were removed by filtration and the filtrate was concentrated under reduced pressure to obtain pure product.

References: [1]Patent: WO2008/8539,2008,A2 .Location in patent: Page/Page column 133.
[2]Patent: US2014/336182,2014,A1 .Location in patent: Paragraph 0308.
[3]Patent: WO2008/124083,2008,A2 .Location in patent: Page/Page column 47.

4
[ 2033-24-1 ]
[ 215364-86-6 ]
[ 149-73-5 ]
[ 952138-16-8 ]

Yield	Reaction Conditions	Operation in experiment
		A two necked round bottomed flask equipped with a reflux condenser was charged with Meldrum's acid (15.6 g, 108 mmol) and trimethyl orthoformate (143 mL) . The reaction mixture was heated 100 0C for 2 h. 4-amino-3-bromo-2-methoxypyridine (22 g, 108 mmol) was added and heating was continued for an additional 4 h at 100 0C. The reaction mixture was allowed to cool to RT, diluted with hexane and filtered to obtain the product as a yellow solid.
		Step 3: 5-[(3-Bromo-2-methoxy-pyridin-4-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione A two necked RBF equipped with a reflux condenser was charged with Meldrum's acid (15.6 g, 108 mmol) and trimethyl orthoformate (143 mL). The reaction mixture was heated 100 C. for 2 h. 4-amino-3-bromo-2-methoxypyridine (22 g, 108 mmol) was added and heating was continued for an additional 4 h at 100 C. The reaction mixture was allowed to cool to RT, diluted with hexane and filtered to obtain the product as a yellow solid.
		Step 3: 5-F(3-Bromo-2-methoxy-pyridin-4-ylamino>methylene1-2.2-dimethyl- ϖ.31dioxane-4.6-dione; A two necked RBF equipped with a reflux condenser was charged with Meldrum's acid (15.6 g, 108 mmol) and trimethyl orthoformate (143 mL). The reaction mixture was heated 100 0C for 2 h. 4-amino-3-bromo-2-methoxypyridine (22 g, 108 mmol) was <n="49"/>added and heating was continued for an additional 4 h at 100 0C. The reaction mixture was allowed to cool to RT, diluted with hexane and filtered to obtain the product as a yellow solid.

References: [1]Patent: WO2008/8539,2008,A2 .Location in patent: Page/Page column 134.
[2]Patent: US2014/336182,2014,A1 .Location in patent: Paragraph 0309.
[3]Patent: WO2008/124083,2008,A2 .Location in patent: Page/Page column 47-48.

5
[ 14432-12-3 ]
[ 215364-86-6 ]

References: [1]Patent: US2014/336182,2014,A1 .
[2]Patent: WO2008/124083,2008,A2 .

6
[ 215364-86-6 ]
[ 952138-18-0 ]

References: [1]Patent: US2014/336182,2014,A1 .
[2]Patent: US2018/244667,2018,A1 .
[3]Patent: WO2008/124083,2008,A2 .
[4]Patent: WO2007/113565,2007,A1 .

7
[ 215364-86-6 ]
[ 952138-17-9 ]

References: [1]Patent: US2014/336182,2014,A1 .
[2]Patent: US2018/244667,2018,A1 .
[3]Patent: WO2008/124083,2008,A2 .
[4]Patent: WO2007/113565,2007,A1 .

8
[ 215364-86-6 ]
[ 952138-19-1 ]

References: [1]Patent: US2014/336182,2014,A1 .
[2]Patent: US2018/244667,2018,A1 .
[3]Patent: WO2008/124083,2008,A2 .
[4]Patent: WO2007/113565,2007,A1 .

9
[ 215364-86-6 ]
[ 100-46-9 ]
3-benzyl-4-methoxy-3H-imidazo[4,5-c]pyridine [ No CAS ]

References: [1]Tetrahedron Letters,2016,vol. 57,p. 2708 - 2712.

10
[ 215364-86-6 ]
[ 100-46-9 ]
C₁₃H₁₅N₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
143 mg	With chloro[2-(dicyclohexylphosphino)-3 ,6-dimethoxy-2’,4’, 6’-triisopropyl- 1,1’-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II); lithium hexamethyldisilazane; In tetrahydrofuran; at 40℃;Inert atmosphere;	General procedure: Step 1: A vial equipped with a magnetic stir bar was charged with the ortho-haloaminopyridine and BrettPhos G1 precatalyst (6 mol %). The vial was sealed with a teflon screw cap, and evacuated and backfilled with argon three times. The amine (1 to 1.5 mol eq) was added via syringe, followed by LiHMDS solution (1M in THF, 2.5 mol eq). Amines that were solid at room temperature were added with the catalyst. The reaction mixture was stirred at 40 C for 4-18 h, until LC/MS indicated complete conversion of the starting material. The mixture was cooled to room temperature, diluted with dichloromethane, and poured into water. The organic phase was separated and the aqueous phase was extracted twice more with dichloromethane. The combined organic phases were dried over Na2SO4. The solvent was removed under reduced pressure.

References: [1]Tetrahedron Letters,2016,vol. 57,p. 2708 - 2712.

11
[ 215364-86-6 ]
3-bromo-5-iodo-2-methoxypyridin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-iodo-succinimide; acetic acid; In acetonitrile; at 20℃; for 16h;	3-bromo-5-iodo-2-methoxypyridin-4-amine (i43): To a stirred solution of <strong>[215364-86-6]3-bromo-2-methoxypyridin-4-amine</strong> (i42) (2.9 g, 14.3 mmol) in acetonitrile (122 mL) and acetic acid (3 ml_), NIS (3.55 g, 15.7 mmol) was added and the reaction was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by silica gel (100:200 mesh) column chromatography using 10% ethyl acetate in n-hexanes as eluent to afford 3-bromo-5-iodo-2-methoxypyridin-4-amine (i43) (4.6 g, Yield 97%). 1H NMR (400 MHz, DMSO-d6) δ 3.82 (s, 3H), 6.07 (s, 2H), 8.05 (s, 1 H). MS (ESI) m/e (M+1 )+: 330.95
92%	With N-iodo-succinimide; acetic acid; In acetonitrile; at 20℃; for 16h;	To a solution of <strong>[215364-86-6]3-bromo-2-methoxypyridin-4-amine</strong> (4.0 g, 19.8 mmol, 1.0 equiv.) in acetonitrile (30 mL) and acetic acid (4.1 mL) was added NIS (4.9 g, 21.7 mmol, 1.1 equiv.), and the reaction mixture was stirred at room temperature for 16 h. Then the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (50 mL x 2). The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluent: PE/EtOAc = 4/1) to afford 3-bromo-5-iodo-2-methoxypyridin- 4-amine (6.0 g, 92% yield) as a white solid. LC-MS: m/z 329 [M+H]+.

References: [1]Patent: WO2016/124508,2016,A1 .Location in patent: Page/Page column 61.
[2]Patent: WO2019/191470,2019,A1 .Location in patent: Paragraph 00614; 00615.
[3]Journal of Medicinal Chemistry,2022,vol. 65,p. 4600 - 4615.

12
[ 215364-86-6 ]
[ 1256833-62-1 ]