433226-06-3|Ethyl 2-amino-5-bromonicotinate| Ambeed

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Quality Control of [ 433226-06-3 ] Purity: 97% SDS Specification

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Product Details of [ 433226-06-3 ]

CAS No. :	433226-06-3
Formula :	C₈H₉BrN₂O₂
M.W :	245.07
SMILES Code :	CCOC(=O)C1=CC(Br)=CN=C1N
MDL No. :	MFCD08276943
InChI Key :	QGADVECLXFPSOE-UHFFFAOYSA-N
Pubchem ID :	18525957

Safety of [ 433226-06-3 ]

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

Computational Chemistry of [ 433226-06-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	52.43
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	65.21 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.09
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	1.97
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.61
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.	1.22
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	1.5
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.68

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.74
Solubility	0.442 mg/ml ; 0.0018 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.	-2.96
Solubility	0.266 mg/ml ; 0.00108 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	-3.0
Solubility	0.242 mg/ml ; 0.000989 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.	-6.4 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)	1.93

Application In Synthesis of [ 433226-06-3 ]

* 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.

Downstream synthetic route of [ 433226-06-3 ]

[ 433226-06-3 ] Synthesis Path-Downstream 1~35

1
[ 433226-06-3 ]
[ 140-88-5 ]
[ 941604-76-8 ]

Yield	Reaction Conditions	Operation in experiment
66%		An acetonitrile (100 tnL) solution of <strong>[433226-06-3]ethyl 2-amino-5-bromonicotinate</strong> (2.46 g, 10 mmol), ethyl acrylate (3.1 mL, 30 mmol) and diisopropylethylamine (5.3 mL, 30 mmol) was purged with Argon for 10 min. Pd(OAc)2 (225 mg, 1 mmol) and P(o-Tol)3 (609 rag, 2 mmol) was added and then the Argon purge was repeated. The mixture was heated to 100 0C and stirred for 4 hours under Argon. Upon cooling, the mixture was evaporated and purified by chromatography (silica, 1-2% MeOH in CH2CI2). Crystallization from a CH2Cl2 /hexane mixture afforded 1.73 g (66%) of the title compound. 1H NMR (300 MHz, CDCl3, delta) 8.36 and 8.33 (2 AA' d, J=2.3 Hz, 2H), 7.58 (d, J=16.0 Hz, IH), 6.32 (d, J=16.0 Hz, IH), 4.37 and 4.26 (2q, J=7.2 Hz, 2x2H), 1.42 and 1.34 (2t, J=7.2 Hz, 2x3H).

References: [1]Patent: WO2007/67416,2007,A2 .Location in patent: Page/Page column 64; 135.

2
[ 13362-26-0 ]
[ 433226-06-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-Bromosuccinimide; In tetrahydrofuran; at 0 - 23℃; for 18h;	[0243] To a stirred solution of compound 11(15 g; 90.36 mmol; 1 eq) in dry THF (150 mL) was added NBS (16 g; 90.36 mmol; 1 eq) in portions at 0 C and the resulting mixture was stirred at 23 C for 18 h. The mixture was poured into ice-cold saturated aqueous NaHCO3 solution and the organic components were extracted with ethyl acetate (3 x 200 mL). The combined organic layers were then washed with brine solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to afford the title compound (22 g, 100%) as an off white solid. 1H NMR (DMSO-d6) oe 8.29 (d, 1H, J = 3 Hz), 8.12 (d, 1H, J = 2 Hz), 7.31 (s, 2H), 4.29 (q, 2H, J = 7 Hz), 1.30 (t, 3H, J = 7 Hz). LCMS: mlz = 245.0 [M+j, 247.0 [M+21, RT = 3.34 minutes, (Program P1, Column W).
98.36%	With N-Bromosuccinimide; In acetonitrile; at 20℃; for 3h;	100 mmol (16.6 g) of ethyl 2-aminonicotinate was reacted with 110 mmol (19.58 g) of N-bromosuccinimide in 200 ml of acetonitrile and reacted at room temperature for three hours. After the completion of the reaction allow to stand for three hours at zero degrees Celsius environment . Suction filtration carried out , filter cake leaching with acetonitrile to obtain 24. 1g of solid, the yield of 98.36%. Acetonitrile spin recovery.
91%	With bromine; sodium hydrogencarbonate; In dichloromethane; at 0℃; for 1h;	A CH2Cl2 (30 mL) solution of bromine (16.8Og, 105 mmol) was added to a CH2Cl2 (ISO mL) suspension of ethyl <2-aminonicotinate (11.64 g, 70 mmol) and NaHCO3 (17.7 g, 210 mmol) at 0 0C. After an hour stirring at this temperature, water (50 mL) was added. The solution was decolorized with a saturated solution OfNaHSO3, extracted with CH2Cl2, dried over MgSO4 and evaporated. Recrystallization from a CH2Cl2 /hexane mixture afforded 16.02 g (91%) of the title compound. 1H NMR (300 MHz, CDCl3, delta) 8.22 (m, 2H), 4.35 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H). MS (ESI) m/e 245 (M + H)+.

	With N-Bromosuccinimide;	Example 125 Synthesis of ethyl 2-amino-5-bromonicotinate. To a solution of ethyl 2-aminonicotinate (25 g, 150.44 mmol) in CH3CN (500 mL) was added NBS (32.1 g, 180.5 mmol) in portions over 30 min at 0 C. The mixture was warmed to RT and stirred for 2 h. The reaction mixture was concentrated. The residue was washed with NaHCO3 aqueous (300 mL) and extracted with EtOAc (300 mL*3), the combined organic layers were concentrated to give ethyl 2-amino-5-bromonicotinate (36.9 g, yield: 100%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M+H]+: 245.1.
	With N-Bromosuccinimide;	Example 71 Synthesis of ethyl 2-amino-5-bromonicotinate. To a solution of ethyl 2-aminonicotinate (500 mg, 3.00 mmol) in dry MeCN (20 mL) was added NBS (643 mg, 3.6 mmol) slowly at RT. The resulting mixture was stirred at RT for 1 h. The reaction was then quenched with H2O (30 mL) and extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product of ethyl 2-amino-5-bromonicotinate (700 mg, yield: 95.2%) as a white solid, which was used in the next step without purification. ESI-MS [M+H]+: 245.0.

References: [1]Patent: WO2015/95128,2015,A1 .Location in patent: Paragraph 0239; 0242; 0243.
[2]European Journal of Medicinal Chemistry,2018,vol. 158,p. 236 - 246.
[3]Patent: CN104402881,2016,B .Location in patent: Paragraph 0022; 0023.
[4]Patent: WO2007/67416,2007,A2 .Location in patent: Page/Page column 64; 134.
[5]Patent: US2019/284182,2019,A1 .
[6]Patent: US2019/284182,2019,A1 .

Yield	Reaction Conditions	Operation in experiment
78%	With lithium hydroxide; In dimethyl sulfoxide; at 120℃; for 1h;Inert atmosphere; Sealed tube;	General procedure: In a 10mL dry sealed reaction tube,Add ethyl 1,2,3-triazine-5-carboxylate 3a (15.3mg, 0.10mmol), ethyl cyanoacetate 2b (13.6mg, 0.12mmol) and lithium hydroxide (0.5mg, 0.02mmol) in this order . The solvent nitrogen was added DMSO (1.0mL) was substituted three times, the reaction tube was sealed was placed 120 reaction 1h. The reaction was monitored by TLC. After the reaction was completed, it was extracted with dichloromethane (3 * 10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. After column chromatography, the target product 13c (16.0 mg, 67%) was obtained.

4
[ 6165-69-1 ]
[ 433226-06-3 ]
[ 1216772-00-7 ]

References: [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 707 - 718.

5
[ 433226-06-3 ]
[ 250726-93-3 ]
[ 1216772-02-9 ]

References: [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 707 - 718.

6
[ 5345-47-1 ]
[ 433226-06-3 ]

References: [1]Patent: WO2015/95128,2015,A1 .

7
[ 433226-06-3 ]
6-bromoimidazo[1,2-a]pyridine-8-carboxylic acid hydrazide [ No CAS ]

References: [1]Patent: WO2015/95128,2015,A1 .

8
[ 433226-06-3 ]
6-bromoimidazo[1,2-a]pyridine-8-carboxylic acid N’-propionylhydrazide [ No CAS ]

References: [1]Patent: WO2015/95128,2015,A1 .

9
[ 433226-06-3 ]
6-bromo-8-(5-ethyl-[1,3,4]oxadiazol-2-yl)imidazo[1,2-a]pyridine [ No CAS ]

References: [1]Patent: WO2015/95128,2015,A1 .

10
[ 433226-06-3 ]
8-(5-ethyl-[1,3,4]oxadiazol-2-yl)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester [ No CAS ]

References: [1]Patent: WO2015/95128,2015,A1 .

11
[ 433226-06-3 ]
3-bromo-8-(5-ethyl-[1,3,4]oxadiazol-2-yl)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester [ No CAS ]

References: [1]Patent: WO2015/95128,2015,A1 .

12
[ 433226-06-3 ]
8-(5-ethyl-[1,3,4]oxadiazol-2-yl)-3-(5-methylthiophen-2-yl)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester [ No CAS ]

References: [1]Patent: WO2015/95128,2015,A1 .

13
[ 433226-06-3 ]
8-(5-ethyl-[1,3,4]oxadiazol-2-yl)-3-(5-methylthiophen-2-yl)imidazo[1,2-a]pyridine-6-carboxylic acid [ No CAS ]

References: [1]Patent: WO2015/95128,2015,A1 .

14
[ 433226-06-3 ]
(S)-N-(1-(4H-1,2,4-triazol-3-yl)ethyl)-8-(5-ethyl-1,3,4-oxadiazol-2-yl)-3-(5-methylthiophen-2-yl)imidazo[1,2-a]pyridine-6-carboxamide [ No CAS ]

References: [1]Patent: WO2015/95128,2015,A1 .

15
[ 107-20-0 ]
[ 433226-06-3 ]
6-bromoimidazo[1,2-a]pyridine-8-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium hydrogencarbonate; In ethanol; water; for 8h;Reflux;	[0245] To a stuffed solution of compound III (22 g; 90 mmol; 1 eq) in ethanol (500 mL) was added sodium bicarbonate (13 g; 179 mmol; 2 eq) and chloroacetaldehyde solution (-50% aqueous solution, 60 mL; 449 mmol; 5 eq) drop wise and the mixture was heated at reflux for 8 h. The mixture was then evaporated to dryness and the pH was adjusted to 7 using ice-cold saturated aqueous NaHCO3 solution and solid NaHCO3. The organic components were extracted from the aqueous layer with ethyl acetate (3 x 700 mL) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and the solvents were removed in vacuo to obtain a dry residue which was purified by silica gel (230-400 mesh) column chromatography using 10-50% ethyl acetate/hexanes to afford the title compound (14.5 g, 60%) as a brown solid. 1H NMR (DMSO-d6) oe 9.16 (s, 1H), 8.02 (s, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 4.38 (q, 2H, J = 7 Hz), 1.30 (t, 3H, J = 7 Hz). LCMS: m/z = 268.8 [M+j, 270.8 [M+21, RT = 2.77 minutes, (Program P1, Column Y).

References: [1]Patent: WO2015/95128,2015,A1 .Location in patent: Paragraph 0239; 0244; 0245.

16
[ 14667-47-1 ]
[ 433226-06-3 ]