Methyl 1H-indole-5-carboxylate

Cat.NO.:A114074 Purity:98%

Product Details of [ 1011-65-0 ]

CAS No. :	1011-65-0
Formula :	C₁₀H₉NO₂
M.W :	175.18
SMILES Code :	COC(=O)C1=CC2=C(NC=C2)C=C1
MDL No. :	MFCD00153023
InChI Key :	DRYBMFJLYYEOBZ-UHFFFAOYSA-N
Pubchem ID :	2737635

Safety of [ 1011-65-0 ]

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

Computational Chemistry of [ 1011-65-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	9
Fraction Csp3	0.1
Num. rotatable bonds	2
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	49.58
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	42.09 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.84
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	1.23
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.95
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.	1.38
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	2.36
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.75

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.08
Solubility	1.45 mg/ml ; 0.00829 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.	-1.71
Solubility	3.4 mg/ml ; 0.0194 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	-3.36
Solubility	0.0772 mg/ml ; 0.000441 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.	-6.5 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)	1.26

Application In Synthesis of [ 1011-65-0 ]

* 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 [ 1011-65-0 ]

[ 1011-65-0 ] Synthesis Path-Downstream 1~10

1
[ 1011-65-0 ]
[ 74-88-4 ]
[ 128742-76-7 ]

Yield	Reaction Conditions	Operation in experiment
97%		Preparation of 1-Methyl-5- [5- (2-phenoxy-ethylsulfanylmethyl)- [1, 3,4] oxadiazol-2-yl]- 1H-indole a) 1-Methyl-lH-indole-5-carboxylic acid methyl ester A DMF solution of methyl indole-5-carboxylate (5.0 g, 28.54 mmol, 1 eq. ) was cooled in an ice bath and then treated with sodium hydride (1.37 g, 34.29 mmol, 1.2 eq. ). After 20 minutes at 0C, the reaction was treated with iodomethane (6.08 g, 2.7 mL, 42. 81 mmol, 1.5 eq. ). After stirring for 4 hours, the reaction was quenched with water. The reaction was extracted twice with 150 mL of ethyl acetate and the organic layers were combined, dried, filtered, and the solvent removed in vacuo leaving a yellow oil that was triturated with hexane to obtain 1-methyl-lH-indole-5-carboxylic acid methyl ester (5.22 g, 97% yield) as a tan solid.
76%		Preparation of methyl 1-methyl-1 f-indoie-5-cari30xylate To a suspension of aH (264 mg, 1.1 mmoi) in DMF (20 ml) was added methyl 1H-indoie-5-carboxylate (1.05 g, 6 mmoi) at 0 QC and the resulting mixture was stirred for 20 minutes, Mel (1.70 g, 2,2 mmo) was added to the reaction mixture, which was then allowed to warm to 50 C overnight. The reaction liquid was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over Na2S04 and concentrated to give the crude product, which was purified by silica gel column (EtQAc/petroleum ether – 1/10) to give the target compound (860 mg, 76%). LCMS: m/z 190.1 [M+Hf,
56%	With sodium hydride; In N,N-dimethyl-formamide; at 0 – 20℃; for 8h;	1H-indole-6-carboxylic acid methyl ester (1.0g, 5.71mmol) was dissolved in dimethylformamide (10ml), and methyl iodide (0.53ml, 8.56mmol) and sodium hydride (374mg, 8.56mmol) were added dropwise thereto at 0. The mixture was stirred for 8 hours at room temperature. 1N hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (600mg, 56%).

		Sodium hydride (1.71 g, 42.80 mmol, 60% in mineral oil) was added at 0 C. in portions to a stirred solution of methyl indole-5-carboxylate (5.0 g, 28.53 mmol, CASRN 1670-81-1) in DMF over a 30 min period. While still at 0 C. MeI (5.33 mL, 85.61 mmol) was added. The resulting mixture was stirred at 0 C. for 60 min then at RT overnight. The mixture was partitioned between H2O and EtOAc and the aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with water, dried (MgSO4), filtered and concentrated to afford 4.91 g of 1-methyl-1H-indole-5-carboxylic acid methyl ester (53).
	With potassium hydride; In tetrahydrofuran; at 20℃; for 0.5h;	Step A. 1-Methyl-indole-5-carboxylic acid methyl ester. Under an atmosphere of nitrogen, a solution of indole-5-carboxylic acid methyl ester (2.5 g, 14.3 mmol) in dry tetrahydrofuran (20 mL) was added dropwise to a stirred slurry of hexane-washed potassium hydride (1.63 g, 14.3 mmol, 35% in oil). When the hydrogen evolution ceased, iodomethane (1.3 mL, 21.5 mmol) was added to the stirred solution. After an additional 30 minutes at room temperature, the precipitate was filtered and washed with diethyl ether. The filtrate was concentrated in vacuo and the residue triturated with hexane to provide the title compound as a yellow solid (2.6 g).
	With sodium hydride; In dimethyl sulfoxide; at 0℃; for 2h;	TE4O was synthesized by the reaction scheme:Methyl 1-methyl-1H-indole-5-carboxylate was prepared according to the article, Org. Lett. 2014, 16, 1124-1127, which is hereby incorporated by reference in its entirety. Rf = 0.49 in hexanes: EtOAc = 2:1. ?HNIVIR (400 MHz, CDC13) ppm 8.4 (s, 1H) 7.9 (d, J 8.6 Hz, 1H) 7.3 (d, J= 9.4 Hz, 1H) 7.1 (d, J= 3.1 Hz, 1H) 6.6 (d, J= 3.9 Hz, 1H) 3.9 (s, 3H)3.8 (s, 3H). ?3C NMR (101 IVIHz, CDC13) ppm 168.2, 139.0, 130.2, 127.9, 123.9, 122.8,121.3, 108.8, 102.6, 51.7, 32.9.

References: [1]Patent: WO2005/40157,2005,A2 .Location in patent: Page/Page column 78.
[2]Journal of the American Chemical Society,2019,vol. 141,p. 12305 – 12311.
[3]Chemistry – A European Journal,2015,vol. 21,p. 1463 – 1467.
[4]Patent: WO2015/74123,2015,A1 .Location in patent: Page/Page column 59-60.
[5]Organic Letters,2006,vol. 8,p. 1339 – 1342.
[6]Patent: WO2014/73904,2014,A1 .Location in patent: Paragraph 894-896.
[7]Journal of Medicinal Chemistry,1992,vol. 35,p. 177 – 184.
[8]Heterocycles,2006,vol. 67,p. 643 – 653.
[9]Patent: US2009/105209,2009,A1 .Location in patent: Page/Page column 56.
[10]Patent: US6344451,2002,B1 .Location in patent: Page column 7.
[11]Organic Letters,2015,vol. 17,p. 2130 – 2133.
[12]Patent: WO2018/237163,2018,A1 .Location in patent: Paragraph 0058; 0059; 0060.

2
hexane-washed potassium hydride [ No CAS ]
[ 1011-65-0 ]
[ 74-88-4 ]
[ 128742-76-7 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran;	Step A. 1-Methyl-indole-5-carboxylic Acid Methyl Ester Under an atmosphere of nitrogen, a solution of indole-5-carboxylic acid methyl ester (2.5 g, 14.3 mmol) in dry tetrahydrofuran (20 mL) was added dropwise to a stirred slurry of hexane-washed potassium hydride (1.63 g, 14.3 mmol, 35% in oil). When the hydrogen evolution ceased, iodomethane (1.3 mL, 21.5 mmol) was added to the stirred solution. After an additional 30 minutes at room temperature, the precipitate was filtered and washed with diethyl ether. The filtrate was concentrated in vacuo and the residue triturated with hexane to provide the title compound as a yellow solid (2.6 g). NMR (CDCl3, 400 MHz): delta 3.82 (s, 3H), 3.93 (s, 3H), 6.58 (dd, 1H), 7.10 (d, 1H), 7.32 (d, 1H), 7.92 (dd, 1H), 8.39 (s, 1H); MS (El, m/z): 189 [M]+, 158, 130.
	In tetrahydrofuran;	Step A. 1-Methyl-indole-5-carboxylic acid methyl ester Under an atmosphere of nitrogen, a solution of indole-5-carboxylic acid methyl ester (2.5 g, 14.3 mmol) in dry tetrahydrofuran (20 mL) was added dropwise to a stirred slurry of hexane-washed potassium hydride (1.63 g, 14.3 mmol, 35% in oil). When the hydrogen evolution ceased, iodomethane (1.3 mL, 21.5 mmol) was added to the stirred solution. After an additional 30 minutes at room temperature, the precipitate was filtered and washed with diethyl ether. The filtrate was concentrated in vacuo and the residue triturated with hexane to provide the title compound as a yellow solid (2.6 g). NMR (CDCl3, 400 MHz): delta 3.82 (s, 3H), 3.93 (s, 3H), 6.58 (dd, 1H), 7.10 (d, 1H), 7.32 (d, 1H), 7.92 (dd, 1H), 8.39 (s, 1H) MS (EI, m/z): 189 [M]+, 158, 130

References: [1]Patent: US6620807,2003,B1 .
[2]Patent: EP1149104,2002,B1 .

3
[ 1480-65-5 ]
[ 1011-65-0 ]
[ 1252779-91-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 200℃; for 2h;Microwave irradiaition;	A mixture of Ij (1.14 mmol, 200 mg), laa (1.14 mmol, 150 mg), K2CO3 (2.28 mmol, 315 mg) and NMP (1.5 mL) was heated at 200 0C in a microwave reactor for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuo. Purification was carried by flash column chromatography (silica gel, 15percent EtO Ac/heptane) to give 290 mg of lbb (290 mg).

References: [1]Patent: WO2010/124082,2010,A1 .Location in patent: Page/Page column 78.

4
[ 1011-65-0 ]
[ 119999-22-3 ]
[ 1423410-73-4 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 1865 – 1877.

5
[ 1011-65-0 ]
[ 119999-22-3 ]
[ 1423410-83-6 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 1865 – 1877.

6
[ 29006-02-8 ]
[ 1011-65-0 ]
methyl 3-(4-methoxybutanoyl)indole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%		To a solution of oxalyl chloride (2.08 g, 16.4 mmol) in dry toluene (10 mL) was added dropwise at 0 C a solution of <strong>[29006-02-8]4-methoxybutyric acid</strong> (1.76 g, 14.9 mmol) in dry toluene (10 mL). After stirring the mixture at room temperature over night, the solvent was distilled off. The residue was dissolved in dry CH2Cl2 (30 mL) and treated with methyl indole-5-carboxylate (801 mg, 4.57 mmol) at room temperature. Then AlCl3 (1.72 g, 12.9 mmol) was added at 0 C and the mixture was stirred at this temperature for 15 min. After addition of water, the reaction mixture was exhaustively extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated. Recrystallization from ethyl acetate gave the pure product (588 mg, 47%). C15H17NO4 (275.3); mp 167-168 C; 1H NMR (DMSO-d6): delta (ppm) 1.83-1.90 (m, 2H), 2.90 (t, 2H, J = 7.3 Hz), 3.21 (s, 3H), 3.37 (t, 2H, J = 6.5 Hz), 3.85 (s, 3H), 7.53 (d, 1H, J = 8.6 Hz), 7.82 (dd, 1H, J = 8.6 Hz and 1.7 Hz), 8.44 (s, 1H), 8.87-8.88 (m, 1H), 12.22 (sbroad, 1H); MS (EI): m/z (%) 275 (4) [M]+, 217 (100).

References: [1]European Journal of Medicinal Chemistry,2017,vol. 125,p. 1107 – 1114.

7
[ 1593-60-8 ]
[ 1011-65-0 ]
[ 1627964-15-1 ]

References: [1]Organic and Biomolecular Chemistry,2017,

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