394223-02-0|Methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate| Ambeed

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Quality Control of [ 394223-02-0 ] Purity: 97% SDS Specification

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Product Details of [ 394223-02-0 ]

CAS No. :	394223-02-0
Formula :	C₉H₈N₂O₂
M.W :	176.17
SMILES Code :	COC(=O)C1=CC2=CC=CN=C2N1
MDL No. :	MFCD08752938
InChI Key :	HWOQCGSIDCQVRM-UHFFFAOYSA-N
Pubchem ID :	17390026

Safety of [ 394223-02-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 394223-02-0 ] 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	1.0
Molar Refractivity	47.37
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	54.98 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.72
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	1.5
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.35
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.	0.9
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	1.84
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.46

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.26
Solubility	0.974 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 (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.26
Solubility	0.963 mg/ml ; 0.00547 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	-2.98
Solubility	0.183 mg/ml ; 0.00104 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.	-6.31 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)	1.67

Application In Synthesis of [ 394223-02-0 ]

* 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 [ 394223-02-0 ]

[ 394223-02-0 ] Synthesis Path-Downstream 1~35

1
(Z)-methyl 2-azido-3-(pyridin-3-yl)acrylate [ No CAS ]
[ 394223-02-0 ]

References: [1]Chemical Communications,2011,vol. 47,p. 2688 - 2690.
[2]Synthesis,2005,p. 2751 - 2757.

2
[ 500-22-1 ]
[ 394223-02-0 ]

References: [1]Synthesis,2005,p. 2751 - 2757.

3
C₁₅H₁₂N₂O₄S [ No CAS ]
[ 394223-02-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol; at 20℃; for 16h;	0.495 g (1.64 mmol) of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid was dissolved in 5 ml of methanol and 3 ml of 2N aqueous sodium hydroxide. The reaction was stirred at 40C for 8 h. The solvent was removed under reduced pressure. Residual volatiles were removed by twice codistilling with toluene. The residue was suspended in methanolic hydrochloric acid and stirred for 16h at RT. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. Yield 0.201 g. MS (Cl+): m/e = 177 (M+H+).

References: [1]Patent: EP1479680,2004,A1 .Location in patent: Page 46.

4
[ 136818-50-3 ]
[ 18107-18-1 ]
[ 394223-02-0 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; hexanes; N,N-dimethyl-formamide;	Acid (3a) (1. Og) was partially dissolved in N, N'-dimethylformamide (20ml) and methanol (2ml) and treated dropwise with trimethylsilyldiazomethane (2M in hexanes, 3.1ml). The mixture was stirred overnight then evaporated. Chromatography on silica using an ethyl acetate and hexane solvent gradient gave the ester (0. 35g). MS (+ve ion electrospray) m/z 177 (MH+).

References: [1]Patent: WO2003/87098,2003,A1 .Location in patent: Page/Page column 40-41.

5
[ 394223-02-0 ]
(1H-pyrrolo[2,3-b]pyridin-2-yl)-methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Ester (3b) (0.34g) in tetrahydrofuran (Sml) was treated dropwise with lithium aluminium hydride (1M in tetrahydrofuran, 1. 9ml) at 0 C. After 2h the mixture was treated with 8% sodium hydroxide, dichloromethane and sodium sulfate, filtered and evaporated. The resulting crude alcohol was dissolved in tetrahydrofuran (4ml) and stirred with manganese (II) oxide (0.74g) for 4h. Filtration and evaporation of solvent gave the aldehyde (lOOmg). MS (+ve ion electrospray) m/z 147 (MH+).
100 mg	With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 22h;Cooling with ice;	To an ice-cold solution of <strong>[394223-02-0]methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate</strong> (300mg) in THF (4.5mL) was added LiAlH4 (1.7mL, 1 M in THF). The ice bath was removed and the reaction mixture was stirred at RT for 2h. LiAlH4 (2.8mL, 1 M in THF) was added and the stirring was pursued for 20h at RT. DCM and 1 M NaOH were added and the phases were separated. The org. layer was dried (Na2SO4) and evaporated in vacuo to afford 100mg of oil. LC-MS (B): tR = 0.34min; [M+H]+: 149.28.
100 mg	With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 22h;Cooling with ice;	To an ice-cold solution of <strong>[394223-02-0]methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate</strong> (300 mg) in THF (4.5 mL) was added LiAlH4 (1.7 mL, 1M in THF). The ice bath was removed and the reaction mixture was stirred at RT for 2 h. LiAlH4 (2.8 mL, 1M in THF) was added and the stirring was pursued for 20 h at RT. DCM and 1M NaOH were added and the phases were separated. The org. layer was dried (Na2SO4) and evaporated in vacuo to afford 100 mg of oil. LC-MS (B): tR=0.34 min; [M+H]+: 149.28.

With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 1h;

[00261] To methyl 1 H-pyrrolo[2,3-b]pyridine-2-carboxylate (1200 mg, 6.81 mmol) was added THF (Volume: 40 ml_), cooled to about 0 C then LAH 2M in THF (5.1 1 ml_, 10.22 mmol) was added. The reaction was allowed to warm to room temperature and stirred at room temperature for 1 hour or until done by LCMS. The reaction was cooled in ice bath, then quenched carefully by adding excess water dropwise (0.8 ml). Then as salts formed magnesium sulfate and then sodium sulfate was added. The reaction was removed from ice bath and stirred for 1 hour, filtered through celite, flushed with THF, and concentrated to residue to give 930 mg of the desired product 2.1a in 92% yield, used as is LC-MS (m/z): 149.1 [M+H]+, 0.19 min.

References: [1]Patent: WO2003/87098,2003,A1 .Location in patent: Page/Page column 41.
[2]Patent: WO2013/114332,2013,A1 .Location in patent: Page/Page column 117.
[3]Patent: US2014/371204,2014,A1 .Location in patent: Paragraph 0841.
[4]Patent: WO2018/73753,2018,A1 .Location in patent: Paragraph 00261.

Yield	Reaction Conditions	Operation in experiment
		(b) Methyl 7-azaindole-2-carboxylate. The acid (17a) (1.0 g) was partially dissolved in DMF (20 ml) and methanol (2 ml) and treated dropwise with trimethylsilyldiazomethane (2M in hexanes, 3.1 ml). The mixture was stirred overnight then evaporated. Chromatography on silica (0-20-50-100% ethyl acetate/hexane) gave the ester (0.35 g). MS (+ve ion electrospray) m/z 177 (MH+).

7
[ 394223-02-0 ]
[ 1086392-34-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine; In methanol; water; at 80℃; for 2h;Heating / reflux;	To a solution of methyl 1 /-/-pyrrolo[2,3-b]pyridine-2-carboxylate (100mg, 0.57mmol) in methanol (10ml) was added hydrazine hydrate (50-60%) (0.39ml, 3.97mmol). The mixture was refluxed at 8O0C for 2h. After cooling to room temperature, the solvent was removed. Trituration with ether gave the title compound as a solid (91 mg).

References: [1]Patent: WO2009/71577,2009,A1 .Location in patent: Page/Page column 52-53.

8
[ 394223-02-0 ]
[ 323594-39-4 ]
1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		0.195 g (1.1 mmol) of <strong>[394223-02-0]1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester</strong> was dissolved in 4 ml of DMF and 48.7mg (1.2 mmol) of sodium hydride (60% in mineral oil) was added. The reaction was stirred at RT for 20 min, cooled to -78C then 324 mg (1.2 mmol) of 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001) 460 pp. WO 0107436 A2] was added. The reaction was allowed to warm to RT overnight. 0.3 ml of 2N aqueous sodium hydroxide was added and the reaction was stirred at RT for 24 h. The product was purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a solid. Yield 280 mg. MS (TOF MS ES+): m/e = 359 (M+).

References: [1]Patent: EP1479680,2004,A1 .Location in patent: Page 46.

9
[ 394223-02-0 ]
[ 68-12-2 ]
[ 1204475-76-2 ]

Yield	Reaction Conditions	Operation in experiment
	With trichlorophosphate;	Example 10Synthesis of 3- (difluoromethyl) -lH-pyrrolo [2 , 3-jb]pyridine-2-carboxylic acid 13 14This sequence commences with the esterification of 2 with diazomethane followed by Vilsmeier-Haack reaction with phosphorus oxychloride and dimethylformamide to produce methyl 3-formyl-lH-pyrrolo [2, 3-i>]pyridine-2-carboxylate (12) . Treatment of 12 with (diethylamino) sulfur trifluoride (DAST) in dichloromethane gives methyl3- (difluoromethyl) -lH-pyrrolo [2 , 3-£>]pyridine-2-carboxylate(13) that is saponified to the corresponding acid by aqueous lithium hydroxide in methanol to afford 3- (difluoromethyl) -lH-pyrrolo [2 , 3 -b] pyridine-2 -carboxylic acid(14) .

References: [1]Patent: WO2010/5528,2010,A2 .Location in patent: Page/Page column 90-91.

10
[ 394223-02-0 ]
[ 1204475-83-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; nitric acid;	Example 14Synthesis of 3 -nitro-lH-pyrrolo [ 2 , 3 -jb] pyridine-2 -carboxylic acidH2SO4 20 21Esterification of 1 with diazomethane followed by nitration with a mixture of concentrated nitric and sulfuric acids gives methyl 3-nitro-lH-pyrrolo [2 , 3-jb]pyridine-2-carboxylate (20) . Hydrolysis with aqueous lithium hydroxide in methanol provides 3-nitro-lff-pyrrolo [2 , 3-jb]pyridine-2-carboxylic acid (21) .

References: [1]Patent: WO2010/5528,2010,A2 .Location in patent: Page/Page column 93.

11
[ 394223-02-0 ]
[ 76513-69-4 ]
[ 1313726-06-5 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of methyl 1 H-pyrrolo[2,3-b]pyrid1 ine-2-carboxylate (H-1) (528 mg, 3 mmol) in dried THF (5 mL) at 0C was added NaH (240 mg, 6 mmol). The reaction was stirred for 0.5 h under N2, and then SEMCI (526 mg, 3 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. H20 was added to quench the reaction. The resulting mixture was extracted with EtOAc. The oragnic layer was dried over Na2SC , and concentrated to afford the title compound (750 mg), which was used for the next step without purification. MS (m/z): 307 (M+1 )+.
		Methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (H'-1) To a solution of <strong>[394223-02-0]methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate</strong> (H-1) (528 mg, 3 mmol) in dried THF (5 mL) at 0 C. was added NaH (240 mg, 6 mmol). The reaction was stirred for 0.5 h under N2, and then SEMCl (526 mg, 3 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. H2O was added to quench the reaction. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, and concentrated to afford the title compound (750 mg), which was used for the next step without purification. MS (m/z): 307 (M+1)+.

References: [1]Patent: WO2011/79804,2011,A1 .Location in patent: Page/Page column 32.
[2]Patent: US2012/245178,2012,A1 .Location in patent: Page/Page column 18.

12
[ 394223-02-0 ]
[ 223376-47-4 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide; In methanol; at 80℃;	To a solution of methyl 1 H-pyrrolo[2,3-b]pyridine-2-carboxylate (H-1 ) (880 mg, 5.0 mmol) in MeOH (2 mL) was added NH3.H20 (6 ml_). The reaction was heated at 80C overnight. After being cooled to room temparature, the mixture was concentrated in vacuo to afford the title compound (805 mg) as a yellow solid, which was used for the next step without further purification. MS (m/z): 162 (M-M )+.
	With ammonium hydroxide; In methanol; at 80℃;	1H-Pyrrolo[2,3-b]pyridine-2-carboxamide (H-2) To a solution of <strong>[394223-02-0]methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate</strong> (H-1) (880 mg, 5.0 mmol) in MeOH (2 mL) was added NH3.H2O (6 mL). The reaction was heated at 80 C. overnight. After being cooled to room temperature, the mixture was concentrated in vacuo to afford the title compound (805 mg) as a yellow solid, which was used for the next step without further purification. MS (m/z): 162 (M+1)+.

References: [1]Patent: WO2011/79804,2011,A1 .Location in patent: Page/Page column 32.
[2]Patent: US2012/245178,2012,A1 .Location in patent: Page/Page column 18.
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 7577 - 7589.

13
[ 394223-02-0 ]
[ 933691-76-0 ]

References: [1]Patent: WO2011/79804,2011,A1 .
[2]Patent: US2012/245178,2012,A1 .
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 7577 - 7589.

14
[ 394223-02-0 ]
[ 1313722-66-5 ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 7577 - 7589.

15
[ 394223-02-0 ]
C₁₂H₁₁BrN₆ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 7577 - 7589.

16
[ 394223-02-0 ]
C₁₂H₈BrN₇ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 7577 - 7589.

17
C₉H₈N₄O₂ [ No CAS ]
[ 394223-02-0 ]

References: [1]Organic Syntheses,2007,vol. 84,p. 262 - 271.

18
[ 394223-02-0 ]
2-(((tert-butyldimethylsilyl)oxy)methyl)-1H-pyrrolo[2,3-b]pyridine [ No CAS ]