1187449-01-9|4-Bromo-5-chloropyridin-2-amine| Ambeed

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Quality Control of [ 1187449-01-9 ] Purity: 95% SDS Specification

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Product Details of [ 1187449-01-9 ]

CAS No. :	1187449-01-9
Formula :	C₅H₄BrClN₂
M.W :	207.46
SMILES Code :	NC1=NC=C(Cl)C(Br)=C1
MDL No. :	MFCD15143360
InChI Key :	VIZMARKIEQIMIG-UHFFFAOYSA-N
Pubchem ID :	53485418

Safety of [ 1187449-01-9 ]

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

Computational Chemistry of [ 1187449-01-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	41.35
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.91 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.57
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	1.82
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.09
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.	1.6
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	2.03
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.82

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.77
Solubility	0.355 mg/ml ; 0.00171 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.	-2.26
Solubility	1.15 mg/ml ; 0.00553 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	-3.14
Solubility	0.15 mg/ml ; 0.000724 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	Yes
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.	-6.27 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)	1.82

Application In Synthesis of [ 1187449-01-9 ]

* 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 [ 1187449-01-9 ]

[ 1187449-01-9 ] Synthesis Path-Downstream 1~35

1
[ 84249-14-9 ]
[ 1187449-01-9 ]

Yield	Reaction Conditions	Operation in experiment
72%	With N-chloro-succinimide; In N,N-dimethyl-formamide; at -20 - 20℃; for 24h;	4-Bromopyridin-2-amine (17.3 g, 100 mmol) was dissolved in DMF (200 mL) and cooled at -20C. NCS (14.7 g, 110 mmol) was added in portions at -20C. The reaction mixture was stirred at rt. for 24 h, and then diluted with WATER (200 mL), extracted with EtOAc (100 mL3). The combined organic layers were washed with saturated brine (100 mL2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated. The residues were purified by column chromatography (eluent: PE:EtOAc, 5:1 to 1:1) to give 15 g of the title compound as a yellow solid (yield: 72%).
61%	With N-chloro-succinimide; In N,N-dimethyl-formamide; at -20 - 20℃; for 24h;	[00252j 27A. 4-Bromo-5-chloropyridin-2-amine: To a stirred solution of 4-bromopyridin-2-amine (30.0 g, 173 mmol) in DMF (350 mL) at -20 C was added 1-chloropyrrolidine-2,5-dione (24.3 g, 182 mmol). The reaction mixture was stirred at rtfor 24 h. The reaction mixture was poured into cold 1 M aq. NaOH (300 mL) andextracted with Et20 (2 x 400 mL). The combined extracts were washed with water (3 x200 mL), brine (200 mL), dried over Na2SO4, filtered, and concentrated. The crudematerial was recrystallized from CH2C12 to provide 27A as red solid (22.0 g, 106 mmol,61% yield). LC-MS Anal. Calc?d for C5H4BrC1N2: 205.93, found [M+H] 206.9.
61%	With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20℃; for 24h;	81A. 4-Bromo-5-chloropyridin-2-amine To a stirred solution of 4-bromopyridin-2-amine (30 g, 173 mmol) in DMF (350 mL) at -20 C. was added 1-chloropyrrolidine-2,5-dione (24 g, 182 mmol). The reaction mixture was allowed to stir at rt for 24 h. The reaction mixture was poured into a cold solution of 1M NaOH (300 mL) and the mixture was extracted with Et2O (2400 mL). The combined extracts were washed with water (3200 mL), brine (200 mL), dried over Na2SO4, filtered and concentrated. The crude material was recrystallized from DCM which afforded 4-bromo-5-chloropyridin-2-amine as red solid (22 g, 106 mmol, 61% yield). LC-MS Anal. Calc'd for C5H4BrClN2 205.93. found [M+H] 206.9. 1H NMR (400 MHz, CDCl3) delta 8.08 (s, 1H), 6.81 (s, 1H), 4.49 (br. s., 2H).

61%	With N-chloro-succinimide; In N,N-dimethyl-formamide; at -20 - 20℃;Inert atmosphere;	Description 14 (D14); 4-bromo-5-chloro-2-pyridinamine; To a stirred solution of 2-amino-4-bromopyridine (15.0 g, 86.7 mmol) in N, N- dimethylformamide (430 ml_) at -200C was added N-chlorosuccinimide (12.99 g, 95.34 mmol). Reaction mixture allowed to stir at room temperature for 24 h. Reaction mixture poured into cold 1 M sodium hydroxide (750 ml_) and extracted with diethyl ether (4 x 500 ml_). The combined extracts were washed with water (3 x 200 ml_), brine (200 ml_), dried over sodium sulfate, filtered and solvent removed in vacuo yielding a solid (17.2 g) which was recrystallised from hexane to yield a solid (12.8 g). Material purified by column <n="70"/>chromatography eluting with 0-25% ethyl acetate in dichloromethane. The relevant fractions were combined and solvent removed in vacuo to furnish the title compound (1 1.0 g, 61 %). 1H NMR: (300 MHz, CDCI3) delta 8.05 (s, 1 H), 6.79 (s, 1 H), 4.49 (s, 2H).
43.7%	With N-chloro-succinimide; In N,N-dimethyl-formamide; at -78 - 20℃;Inert atmosphere;	N-Chloro-succinimide (3.70 g, 27.7 mmol) dissolved in DMF (20 mL) was added dropwise to 4-bromopyridin-2-amine (4.40 g, 25.4 mmol) in DMF (50 mL) at -78 C. over a period of 30 minutes under nitrogen. The resulting suspension was then allowed to warm to r.t. After stirring under these conditions for 24 h, the reaction mixture was diluted with Et2O (50 mL) and washed sequentially with 1 M aqueous NaOH (2×50 mL), water (50 mL), and saturated aqueous sodium chloride (25 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in DCM. Pure fractions were evaporated to dryness to afford 4-bromo-5-chloropyridin-2-amine (2.30 g, 43.7%) as a cream solid. 1H NMR (400 MHz, DMSO-d6, 30 C.) 6.35 (2H, s), 6.82 (1H, s), 8.01 (1H, s). m/z: ES+[M+H]+ 209 (35C1 81Br and 37C1 79Br isotopes).
	With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20℃; for 12h;	To a solution of 4-bromopyridin-2-amine (500 mg, 2.89 mmol) in N,N-dimethylformamide (5 mL) was added N-chlorosuccinimide (463 mg, 3.47 mmol) and the mixture was stirred at room temperature for 12 hours. The mixture was filtered through diatomaceous earth and concentrated and the residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude title compound. Purification by column chromatography (silica gel, 30 % ethyl acetate in hexane) afforded the title compound.
	With N-chloro-succinimide; In N,N-dimethyl-formamide; at -20 - 20℃; for 16h;	To a solution of 4-bromopyridin-2-amine (12.0 g, 69.4 mmol) in N,N-dimethylformamide (200 mL) at -20 C. was slowly added a solution of 1-chloropyrrolidine-2,5-dione (10.24 g, 77.0 mmol) in N,N-dimethylformamide (200 mL). The mixture was stirred at room temperature for 16 hours and the mixture was poured into cold 1M aqueous sodium hydroxide (1000 mL) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography on silica (Analogix 280), eluting with a gradient of 5-65% ethyl acetate/hexanes gave the title compound. MS (ESI) m/e 208 (M+H)+.
	With N-chloro-succinimide; In N,N-dimethyl-formamide; at -20 - 20℃; for 24h;	General procedure: 5.2.2.30 7,8-Dichloro-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) To a solution of 2-amino-4-chloropyridine (1.28 g, 10.0 mmol) in DMF (40 mL) at -20 C was added NCS (2.67 g, 20.0 mmol). This mixture was allowed to warm to room temperature and stirred for 24 h, and then poured into 300 mL ice-water and extracted with ethyl acetate. The extracts were washed with 1 M NaOH and brine, dried and evaporated. The residue was purified by column chromatography on silica gel to give 4,5-dichloropyridin-2-amine (1.12 g, 69.0%).

References: [1]Patent: EP3556761,2019,A1 .Location in patent: Paragraph 0102; 0105.
[2]Patent: WO2014/78609,2014,A1 .Location in patent: Paragraph 00252.
[3]Patent: US9133163,2015,B2 .Location in patent: Page/Page column 89; 90.
[4]Patent: WO2009/112473,2009,A1 .Location in patent: Page/Page column 68-69.
[5]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2552 - 2555.
[6]Patent: US2016/376287,2016,A1 .Location in patent: Paragraph 0624.
[7]Journal of Medicinal Chemistry,2015,vol. 58,p. 9663 - 9679.
[8]Patent: WO2014/139328,2014,A1 .Location in patent: Page/Page column 381.
[9]Patent: US2014/275011,2014,A1 .Location in patent: Paragraph 1521.
[10]European Journal of Medicinal Chemistry,2016,vol. 117,p. 19 - 32.

2
[ 1187449-01-9 ]
[ 1187449-04-2 ]

Yield	Reaction Conditions	Operation in experiment
78%	With Iodine monochloride; In N,N-dimethyl-formamide; at 40℃; for 31h;Inert atmosphere;	Description 15 (D15); 4-bromo-5-chloro-3-iodo-2-pyridinamine; To a stirred solution of <strong>[1187449-01-9]4-bromo-5-chloro-2-pyridinamine</strong> D14) (1 1.0 g, 48.2 mmol) in N, N- dimethylformamide (430 ml_) at 400C was added iodine monochloride (9.40 g, 57.9 mmol) and allowed to stir at this temperature for 3 h. A further portion of iodine monochloride(9.40 g, 57.9 mmol) was added and allowed to stir at the same temperature for 24 h.Additional iodine monochloride (4.70 g, 28.9 mmol) added and reaction mixture allowed to stir for 4 h at 400C. Reaction mixture poured into water (1500 mL), upon addition a precipitate formed. Solid isolated, washed with water (500.00 cm3), dissolved in dichloromethane (1600 mL) and washed with 10% sodium thiosulfate solution (2 x 250 mL). Organic portion dried over sodium sulfate, filtered and solvent removed in vacuo yielding a solid (16.2 g). Material purified by column chromatography eluting with 75-100% dichloromethane in hexane followed by 1% ethyl acetate in dichloromethane. The relevant fractions were combined and solvent removed in vacuo yielding the title compound (13.8 g, 78%).1H NMR: (300 MHz, CDCI3) delta 8.00 (s, 1 H), 5.16 (s, 2H).
50%	With Iodine monochloride; In N,N-dimethyl-formamide; at 40℃;	4-Bromo-5-chloropyridin-2-amine (15 g, 72 mmol) was dissolved in DMF (200 mL) and heated to 40C. Then ICl (12.2 g, 75 mmol) was added and stirred for 4 hours at 40C. ICl (13 g, 80 mmol) was supplemented and then stirred for another 4 hours, and then a third ICl (13 g, 80 mmol) was added and stirred overnight at 40C. After completion of the reaction, the reaction mixture was cooled to rt., diluted with water (200 mL), and extracted with DCM (200 mL3). The combined organic layers were washed with an aqueous solution of sodium thiosulfate (100 mL3) and saturated brine (100 mL*2), dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated. The residues were purified by column chromatography (eluent: PE : EtOAc, 5:1 to 1:1) to give 12g of the title compound as claybank solid (yield: 50%).
	With Iodine monochloride; In N,N-dimethyl-formamide; at 40℃;	A solution of Example 52A (3 g, 14.46 mmol) in N,N-dimethylformamide (60 mL) was heated to 40C and iodine chloride (2.82 g, 17.35 mmol) was added. After stirring at 40C for 3 hours, a second lot of iodine chloride (2.82 g, 17.35 mmol) was added and the mixture was stirred overnight at 40C. The mixture was cooled to room temperature and quenched with ice cold water. The mixture was extracted with ethyl acetate (100 mL x 2) and the organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 20 % ethyl acetate in hexane) afforded the title compound. LCMS: 334.6 (M+H)+.

References: [1]Patent: WO2009/112473,2009,A1 .Location in patent: Page/Page column 69.
[2]Patent: EP3556761,2019,A1 .Location in patent: Paragraph 0102; 0106.
[3]Patent: WO2014/139328,2014,A1 .Location in patent: Page/Page column 396.

3
[ 1187449-01-9 ]
[ 761446-44-0 ]
[ 1226795-88-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2552 - 2555.

4
[ 1187449-01-9 ]
4-((3,4-cis)-4-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-5-chloro-2-methoxypyridine [ No CAS ]

References: [1]Patent: WO2014/78609,2014,A1 .

5
[ 1187449-01-9 ]
(3,4-cis)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-ol [ No CAS ]

References: [1]Patent: WO2014/78609,2014,A1 .

6
[ 1187449-01-9 ]
[ 1610033-94-7 ]

References: [1]Patent: WO2014/78609,2014,A1 .

7
[ 1187449-01-9 ]
[ 1610033-99-2 ]

References: [1]Patent: WO2014/78609,2014,A1 .
[2]Patent: US9133163,2015,B2 .

8
[ 1187449-01-9 ]
[ 1610034-00-8 ]

References: [1]Patent: WO2014/78609,2014,A1 .
[2]Patent: US9133163,2015,B2 .

9
[ 1187449-01-9 ]
2-((2R)-1-(4-(((3,4-trans)-1-(5-chloro-2-methoxypyridin-4-yl)-3-fluoropiperidin-4-yl)oxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile [ No CAS ]

References: [1]Patent: WO2014/78609,2014,A1 .

10
[ 1187449-01-9 ]
(3,4-cis)-1-(5-chloro-2-methoxypyridin-4-yl)-3-(hydroxymethyl)piperidin-4-ol [ No CAS ]

References: [1]Patent: WO2014/78609,2014,A1 .

11
[ 1187449-01-9 ]
(3,4-cis)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(5-chloro-2-methoxypyridin-4-yl)piperidin-4-ol [ No CAS ]

References: [1]Patent: WO2014/78609,2014,A1 .

12
[ 1187449-01-9 ]
methyl 2-((2R,4R)-1-(4-(((3,4-trans)-3-(((tertbutyldiphenylsilyl)oxy)methyl)-1-(5-chloro-2-methoxypyridin-4-yl)piperidin-4-1-(5-chloro-2-methoxypyridin-4-yl)piperidin-4-yl)oxy)phenyl)-4-methoxypyrrolidin-2-yl)acetate [ No CAS ]

References: [1]Patent: WO2014/78609,2014,A1 .

13
[ 1187449-01-9 ]
[ 1610035-71-6 ]

References: [1]Patent: WO2014/78609,2014,A1 .

14
[ 1187449-01-9 ]
[ 1610035-80-7 ]

References: [1]Patent: WO2014/78609,2014,A1 .

15
[ 1187449-01-9 ]
[ 1610035-84-1 ]

References: [1]Patent: WO2014/78609,2014,A1 .

16
[ 1187449-01-9 ]
[ 1610036-07-1 ]

References: [1]Patent: WO2014/78609,2014,A1 .

17
[ 1187449-01-9 ]
2-((2S,4R)-1-(4-(((3,4-trans)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methoxypyrrolidin-2-yl)acetonitrile [ No CAS ]

References: [1]Patent: WO2014/78609,2014,A1 .

18
[ 67-56-1 ]
[ 1187449-01-9 ]
[ 1211534-25-6 ]

Yield	Reaction Conditions	Operation in experiment
84%		[00253j 27B. 4-Bromo-5-chloro-2-methoxypyridine: To MeOH (390 mL) at 0 °C was added TMS-C1 (49.0 mL, 386 mmol). The reaction mixture was warmed to rt and stirred for 30 mm. To this solution was added 27A (20.0 g, 96.0 mmol). The reaction mixturewas stirred for 15 mill and then NaNO2 (2.74 g, 39.8 mmol) was added to the mixture at rt. The reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was concentrated. The residue was diluted with EtOAc and then basified to pH = 11-13 with 1 N aq. NaOH and extracted with EtOAc (3x). The combined organic layers wereconcentrated. Purification by recrystallization from MeOH and water afforded 27B as white needles (18.0 g, 81.0 mmol, 84percent yield). LC-MS Anal. Calc?d for C6H5BrC1NO:220.92, found [M+H] 223.9.
84%		81B. 4-Bromo-5-chloro-2-methoxypyridine To MeOH (390 mL) was added chlorotrimethylsilane (49 mL, 386 mmol) at 0° C., and the solution was warmed to rt and stirred for 30 min. To the resulting solution was added 4-bromo-5-chloropyridin-2-amine (20 g, 96 mmol), and the mixture was stirred for 15 min. To the reaction mixture was added sodium nitrite (2.7 g, 40 mmol) and the solution was stirred at 50° C. for 3 h. The reaction mixture was evaporated in vacuo, and the residue was diluted with EtOAc. The pH of the aqueous layer was adjusted to pH=?12 via addition of 1 N NaOH, and the solution was extracted 3* with EtOAc. The combined organic layers were concentrated, and the residue was purified via recrystallization from MeOH and H2O to give 4-bromo-5-chloro-2-methoxypyridine as white crystalline needles (18 g, 81 mmol, 84percent yield). LC-MS Anal. Calc'd for C6H5BrClNO 222.92. found [M+H] 223.9. 1H NMR (400 MHz, CDCl3) delta 8.18 (s, 1H), 7.08 (s, 1H), 3.94 (s, 4H).

References: [1]Patent: WO2014/78609,2014,A1 .Location in patent: Paragraph 00253.
[2]Patent: US9133163,2015,B2 .Location in patent: Page/Page column 90.

19
[ 1187449-01-9 ]
(3R)-N-{5-chloro-4-[3-(tetrahydro-2H-pyran-4-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl]pyridin-2-yl}piperidine-3-carboxamide [ No CAS ]