133427-07-3|Methyl imidazo[1,2-a]pyridine-8-carboxylate| Ambeed

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Quality Control of [ 133427-07-3 ] Purity: 98% SDS Specification

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Product Details of [ 133427-07-3 ]

CAS No. :	133427-07-3
Formula :	C₉H₈N₂O₂
M.W :	176.17
SMILES Code :	COC(=O)C1=CC=CN2C=CN=C12
MDL No. :	MFCD09842621
InChI Key :	UJLRMEAGEVCFNJ-UHFFFAOYSA-N
Pubchem ID :	15098894

Safety of [ 133427-07-3 ]

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

Computational Chemistry of [ 133427-07-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	9
Fraction Csp3	0.11
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	46.47
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	43.6 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.78
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	1.61
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.12
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.	0.63
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	0.76
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.18

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.33
Solubility	0.83 mg/ml ; 0.00471 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.	-2.14
Solubility	1.28 mg/ml ; 0.00729 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	-2.16
Solubility	1.22 mg/ml ; 0.00693 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.	-6.23 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	1.0
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)	1.53

Application In Synthesis of [ 133427-07-3 ]

* 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 [ 133427-07-3 ]

[ 133427-07-3 ] Synthesis Path-Downstream 1~25

1
[ 67-56-1 ]
[ 136117-70-9 ]
[ 133427-07-3 ]

References: [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 1556 - 1567.

2
[ 133427-07-3 ]
[ 136117-74-3 ]

Yield	Reaction Conditions	Operation in experiment
55%		[0165] To a solution of methyl imidazo[l,2-a]pyridine-8-carboxylate (1.76 g, 10 mmol) in toluene was added DIBAL (IM/THF, 20 ml) at -78 C dropwise. The mixture was stirred at - 78 C for 1 h, quenched with MeOH (2 mL) and saturated NH4CI solution (50 mL) and warmed up to rt. The mixture was continued to stir at rt for 1 h and diluted with DCM (60 mL). The aqueous layer was extracted with DCM (60 mL) twice. The combined organic layer was dried over MgS04 and concentrate. The residue was purified on silica gel with 10 %MeOH/DCM to give imidazo[l,2-a] pyridine- 8-carbaldehyde (0.8g, 55%). LRMS (M+lf) m/z 147.1.

References: [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 1556 - 1567.
[2]Patent: WO2013/102142,2013,A1 .Location in patent: Paragraph 0165.

3
[ 24517-64-4 ]
[ 133427-07-3 ]

References: [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 1556 - 1567.

4
[ 133427-07-3 ]
[ 136117-78-7 ]

References: [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 1556 - 1567.

5
[ 133427-07-3 ]
[ 136117-76-5 ]

References: [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 1556 - 1567.

6
[ 133427-07-3 ]
[ 136117-87-8 ]

References: [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 1556 - 1567.

7
[ 133427-07-3 ]
[ 136117-91-4 ]

References: [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 1556 - 1567.

8
[ 107-20-0 ]
[ 14667-47-1 ]
[ 7440-44-0 ]
[ 133427-07-3 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; for 18h;Heating / reflux;	A mixture of methyl 2-aminonicotinate (WO 89/01488 pg 33, prep 17) (1 g, 6.56 mmol), and chloroacetaldehyde (1.05 ml, 6.56 mmol) in ethanol (5 ml) was heated under reflux for 18 hours. The cooled mixture was diluted with water (10 ml), 0.88 ammonia (1 ml) added and the solution concentrated under reduced pressure. The residue was dissolved in methanol and the dark solution treated with charcoal, the mixture filtered and the filtrate evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (97:2.5:0.5) as eluant, and the product triturated with ether, to afford the title compound, 768 mg. 1H-NMR (CDCl3, 400 MHz) delta: 4.02 (s, 3H), 6.83 (s, 1H), 7.63 (s, 1H), 7.79 (s, 1H), 8.00 (d, 1H), 8.31 (d, 1H). LRMS: m/z TSP+ 177.2 [MH+]

References: [1]Patent: US2005/20611,2005,A1 .Location in patent: Page/Page column 28.

9
[ 17739-45-6 ]
[ 133427-07-3 ]
cis-5-fluoro-N-(4-{5-methyl-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoylamino}-cyclohexyl)-2-(tetrahydro-thiopyran-4-yloxy)-nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20 - 60℃; for 22h;	A mixture of the phenol from example 22 (1.29 g, 2.65 mmol), potassium carbonate (690 mg, 5 mmol), and 2-(2-bromoethoxy)tetrahydro-2H-pyran (840 mg, 4 mmol) in 1-methyl-2-pyrrolidinone (10 ml), was heated at 60 C. for 4 hours, followed by a further 18 hours at room temperature. The mixture was diluted with ethyl acetate and washed with water (*3), then brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as the eluant to afford the title compound as a white foam, 1.20 g. 1H-NMR (CDCl3, 400 MHz) delta: 1.37 (m, 2H), 1.46 (m, 2H), 1.61 (m, 4H), 1.76 (m, 4H), 1.92 (m, 4H), 2.33 (s, 3H), 2.43 (m, 2H), 2.72 (m, 4H), 3.39 (m, 1H), 3.72 (m, 1H), 3.86 (m, 1H), 4.13 (m, 3H), 4.30 (t, 2H), 4.54 (m, 1H), 5.24 (m, 1H), 6.87 (d, 1H), 7.21 (d, 1H), 8.04 (m, 3H), 8.13 (d, 1H), 8.26 (dd, 1H). LRMS: m/z APCI- 614 [M-H-]

References: [1]Patent: US2005/20611,2005,A1 .Location in patent: Page/Page column 43.

10
[ 107-20-0 ]
[ 14667-47-1 ]
[ 133427-07-3 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; for 18h;Heating / reflux;	[0306] A mixture of methyl 2-aminonicotinate (prepared according to the method of WO 89/01488 at page 33, prep 17) (1 g, 6.56 mmol), and chloroacetaldehyde (1.05 mL, 6.56 mmol) in ethanol (5 mL) was heated under reflux for 18 hours. The cooled mixture was diluted with water (10 mL), 0.88 ammonia (1 mL) added and the solution concentrated in vacuo. The residue was dissolved in methanol and the dark solution treated with charcoal, the mixture filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (97:2.5:0.5) as eluant, and the product triturated with ether, to afford the title compound, 768 mg. [0307] 1HNMR (CDCl3, 400 MHz): 4.02 (s, 3H), 6.83 (s, 1H), 7.63 (s, 1H), 7.79 (s, 1H), 8.00 (d, 1H), 8.31 (d, 1H). [0308] MS TSP+ m/z 177.2 [MH+]
	In ethanol; for 18h;Heating / reflux;	[0302] [C00008] [00008] [0303] A mixture of methyl 2-aminonicotinate (WO 89/01488 pg33, prep 17) (1 g, 6.56 mmol), and chloroacetaldehyde (1.05 mL, 6.56 mmol) in ethanol (5 mL) was heated under reflux for 18 hours. The cooled mixture was diluted with water (10 mL), 0.88 ammonia (1 mL) added and the solution concentrated in vacuo. The residue was dissolved in methanol and the dark solution treated with charcoal, the mixture filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (97:2.5:0.5) as eluant, and the product triturated with ether, to afford the title compound, 768 mg. [0304] 1H NMR (CDCl3, 400MHz): delta:4.02 (s, 3H), 6.83 (s, 1H), 7.63 (s, 1H), 7.79 (s, 1H), 8.00 (d, 1H), 8.31 (d, 1H). [0305] MS TSP+m/z 177.2 [MH+]
	With sodium hydrogencarbonate; In ethanol; water; for 18h;Reflux; Inert atmosphere;	[0154] To a solution of methyl 2-amino-pyridine-3-carboxylate (5 g, 35 mmol, 1.0 eq) in ethanol (250 mL) was added NaHC03 (5.08 g) and chloroacetaldehyde in water (35 mL of 45% in water, 148 mmol, 4.5 eq). The reaction mixture was heated at reflux for 18 h. Solvent was removed and the residue was basified with Na2C03 and then extracted with DCM. Organic layers were combined and evaporated to give a residue, which was purified by column to give the titled compound.

References: [1]Patent: US2005/20626,2005,A1 .Location in patent: Page 16.
[2]Patent: US2005/20639,2005,A1 .Location in patent: Page 15.
[3]Patent: WO2013/102142,2013,A1 .Location in patent: Paragraph 0154.

11
[ 133427-07-3 ]
[ 133427-08-4 ]

Yield	Reaction Conditions	Operation in experiment
		The solution was concentrated under reduced pressure to remove the methanol, the aqueous solution acidified using 2N hydrochloric acid, and the mixture evaporated under reduced pressure to give the title compound as a yellow solid. 1H-NMR (DMSO-d6, 400 MHz) delta: 7.60 (dd, 1H), 8.10 (s, 1H), 8.41 (d, 1H), 8.55 (s, 1H), 9.18 (d, 1H) LRMS: m/z ES+ 163 [MH]+
		[0310] Lithium hydroxide solution (2.5 mL, 1M in water) was added to a solution of the ester from preparation 8 (400 mg, 2.27 mmol) in methanol (5 mL) and the solution stirred at room temperature for 90 minutes. The solution was concentrated in vacuo to remove the methanol, the aqueous solution acidified using 2M hydrochloric acid, and the mixture concentrated in vacuo to give the title compound as a yellow solid. [0311] 1HNMR (DMSO-D6, 400 MHz): 7.60 (dd, 1H), 8.10 (s, 1H), 8.41 (d, 1H), 8.55 (s, 1H), 9.18 (d, 1H) [0312] MS TSP+ m/z 163 [MH]+
		[0306] [C00009] [00009] [0307] Lithium hydroxide solution (2.5 ml, 1M in water) was added to a solution of the ester from preparation 3 (400 mg, 2.27 mmol) in methanol (5 ml) and the solution stirred at room temperature for 90 minutes. The solution was concentrated in vacuo to remove the methanol, the aqueous solution acidified using 2M hydrochloric acid, and the mixture evaporated under reduced pressure to give the title compound as a yellow solid. [0308] 1H NMR (DMSO-D6, 400 MHz): delta: 7.60 (dd, 1H), 8.10 (s, 1H), 8.41 (d, 1H), 8.55 (s, 1H), 9.18 (d, 1H) [0309] MS TSP+m/z 163 [MH]+

References: [1]Patent: US2005/20611,2005,A1 .Location in patent: Page/Page column 28.
[2]Patent: US2005/20626,2005,A1 .Location in patent: Page 16.
[3]Patent: US2005/20639,2005,A1 .Location in patent: Page 15.

12
[ 14667-47-1 ]
[ 133603-12-0 ]
[ 133427-07-3 ]

Yield	Reaction Conditions	Operation in experiment
55%	With hydrogen bromide; sodium hydrogencarbonate; In ethanol;	Example 1 Syntheses of methyl imidazo[1,2-a]pyridine-8-carboxylate (Compound No. 1-1) 47% Hydrogen bromide (2.5ml, 14.4 m moles) was added to diethoxybromoethane (2.0ml, 13.2 m moles), and the mixture was stirred at 50 C. for 2 hours. The reaction mixture was cooled to room temperature, and ethanol (7.0 ml) and sodium bicarbonate (1.0 g, 11.9 m moles) were added thereto. The mixture was stirred, and insoluble substance was filtered off. To the filtrate were added methyl 2-aminonicotinate (1.0 g, 6.6 m moles), sodium bicarbonate (2.0 g, 13.8 m moles) and ethanol (7.0 ml), and the mixture was refluxed under heating for 4 hours. The reaction mixture was cooled to room temperature, and saturated aqueous solution of sodium bicarbonate was added thereto. The mixture was extracted with dichloromethane (100 ml*3), and the extract was washed with water, dried over anhydrous magnesium sulfate (MgSO4) and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (eluent: chloroform and then chloroform/methanol=9/1) to give the object compound (0.6 g, yield 55%) as yellow crystals. m.p. 67-69 C.

References: [1]Patent: US5498774,1996,A .

13
[ 5345-47-1 ]
[ 133427-07-3 ]

References: [1]Patent: WO2011/56440,2011,A1 .

14
[ 133427-07-3 ]
[ 885276-95-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-iodo-succinimide; In acetonitrile; at 20℃; for 2h;	A mixture of imidazo[l,2-a]pyridine-8-carboxylic acid methyl ester (3.24 g, 18.3 mmol) and N-iodosuccinimide ( S) (4.11 g, 18.3 mmol) in acetonitrile (50 mL) is stirred at room temperature. After 2 hours, the reaction mixture is quenched with saturated aqueous Na2S2C>3 and extracted with EtOAc (3 x 100 mL). The combined organic layers are washed with water, brine, dried over Na2S04 and concentrated. The crude material is purified by silica gel chromatography eluting with 80% EtOAc in hexanes to afford 3-iodo-imidazo[l,2-a]pyridine-8-carboxylic acid methyl ester. Mp: 99-110C.

References: [1]Patent: WO2011/56440,2011,A1 .Location in patent: Page/Page column 46-47.

15
[ 133427-07-3 ]
[ 1300022-42-7 ]

References: [1]Patent: WO2011/56440,2011,A1 .

16
[ 67-56-1 ]
[ 133427-08-4 ]
[ 133427-07-3 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; for 8h;Reflux;	To a stirred solution of imidazo[l,2-a]pyridine-8-carboxylic acid (3.8 g, 23 mmol) in methanol (100 mL) is added thionylchloride (8.36 g, 70.3 mmol) and the mixture is warmed at reflux. After 8 hours, the reaction mixture is cooled to room temperature and quenched with saturated aqueous NaHCC>3, and extracted with EtOAc (3 x 250 mL). The combined organic layers are washed with water, brine, dried over Na2S04 and concentrated. The crude material is purified by silica gel chromatography eluting with 3% MeOH in CH2CI2 to afford imidazo[l,2-a]pyridine-8-carboxylic acid methyl ester. Mp: 71-73C.

References: [1]Patent: WO2011/56440,2011,A1 .Location in patent: Page/Page column 46-47.

17
[ 133427-07-3 ]
[ 1446321-39-6 ]