341988-36-1|Methyl indoline-6-carboxylate| Ambeed

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Quality Control of [ 341988-36-1 ] Purity: 95% SDS Specification

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Product Details of [ 341988-36-1 ]

CAS No. :	341988-36-1
Formula :	C₁₀H₁₁NO₂
M.W :	177.20
SMILES Code :	O=C(C1=CC2=C(C=C1)CCN2)OC
MDL No. :	MFCD07371629
InChI Key :	IVFIWGSRKYSLLR-UHFFFAOYSA-N
Pubchem ID :	16244446

Safety of [ 341988-36-1 ]

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

Computational Chemistry of [ 341988-36-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.3
Num. rotatable bonds	2
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	52.81
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.33 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.97
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	1.94
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.87
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.	1.55
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	2.0
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.67

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.37
Solubility	0.755 mg/ml ; 0.00426 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.	-2.37
Solubility	0.757 mg/ml ; 0.00427 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	-3.07
Solubility	0.149 mg/ml ; 0.000843 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.	-6.0 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)	1.61

Application In Synthesis of [ 341988-36-1 ]

* 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 [ 341988-36-1 ]

[ 341988-36-1 ] Synthesis Path-Downstream 1~36

1
[ 50820-65-0 ]
[ 341988-36-1 ]

Yield	Reaction Conditions	Operation in experiment
77%		Step 1: A solution of indole-6-carboxylic acid methyl ester (534 mg, 3.05 mmol) in acetic acid (7.5 ml) was cooled to 0° C. Sodium cyanoborohydride (580 mg, 9.2 mmol, 3 equiv.) was added and the mixture stirred at 15° C. for 40 min. A further aliquot of sodium cyanoborohydride (193 mg, 3.05 mmol, 1 equiv.) was added, and the reaction mixture was stirred for 30 min. at room temperature. The solvent was then evaporated, and the residue dissolved in dichloromethane and washed with 1N NaOH. The organic phase was dried with Na2SO4 and evaporated, yielding 2,3-dihydro-1H-indole-6-carboxylic acid methyl ester as a light yellow solid, 494 mg (77percent). This was used as such in the following reaction.
77%		A solution of indole-6-carboxylic acid methyl ester (534 mg, 3.05 mmol) in acetic acid (7.5 ml) was cooled to 0° C. Sodium cyanoborohydride (580 mg, 9.2 mmol, 3 equiv.) was added and the mixture stirred at 15° C. for 40 min. A further aliquot of sodium cyanoborohydride (193 mg, 3.05 mmol, 1 equiv.) was added, and the reaction mixture was stirred for 30 min. at room temperature. The solvent was then evaporated, and the residue dissolved in dichloromethane and washed with 1N NaOH. The organic phase was dried with Na2SO4 and evaporated, yielding 2,3-dihydro-1H-indole-6-carboxylic acid methyl ester as a light yellow solid, 494 mg (77percent). This was used as such in the following reaction.
76%	With sodium cyanoborohydride; acetic acid; at 20℃;	The title compound was prepared according to General Procedure G from methyl indoe~6- carboxylate (200 mg, 1.14 mmo). The crude product was purified b Combifiash silica gel chromatography (0-30percent of EtOAc in hexane), which provided 153 mg (76percent) of the title compound as a colorless solid; NMR (400 MHz, CD ) delta - 7.51 (dd, J = 1,5, 7.6 Hz, 1 H), 7.39 (d, J ~ 15 Hz, 1 H), 7.19 (d, J = 7.6 Hz, 1 H), 3.89 (s, 3 H), 3.67 ( , J = 8,5 Hz, 2 H), 3.12 (t, J *= 8,5 Hz, 2 H). General Procedure 6; Reduction of indole in indolin-e. To the solution of indole (1 eq.) in AcOH (C; 0,5 rnmo) at room temperature was added N38H3CN (3 eq.). The reaction was stirred at the same temperature for 2~4h, The completion of the reaction was monitored by HPLC. Upon completion, H2O was added and the reaction mixture was concentrated to dryness. H2O was added to the crude residue and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCCh, brine and dried over a^SQ^ Filtratio and removal of the solvent provided the desired product, which was used without further purification or purified by Combiflash silica gel chromatography to give the corresponding products.

75%	With sodium cyanoborohydride; acetic acid; In dichloromethane; at 0 - 25℃;	NaCNBH3 (11.49 g; 0.04 equiv.) was added at 0° C., over a period of 10 minutes, to a solution of methyl 1H-indole-6-carboxylate (8 g; 1 equiv.) in acetic acid (80 ml). The reaction mixture was stirred at 0° C. for 20 minutes and then warmed to room temperature and stirred for 1 hour at room temperature. When the conversion was complete, the acetic acid was distilled off under reduced pressure and the resulting residue was dissolved in dichloromethane. The resulting phases were separated. The organic phase was washed with 1N sodium hydroxide solution and dried over sodium sulfate. After removal of the solvent under reduced pressure, purification was carried out by column chromatography (silica gel, 10-15percent ethyl acetate/hexane). Methyl indoline-6-carboxylate (6 g; 75percent) was obtained in the form of a solid.
73%	With sodium cyanoborohydride; acetic acid; at 15℃; for 5h;	A solution of methyl lH-indole-6-carboxylate ( 4.80 g, 27.4 mmol ) in acetic acid ( 40 mL ) was cooled to 15 0 C and then treated with sodium cyanoborohydride ( 6.90 g, 0.11 mmol ) added in small portions over 30 min. After 5 h at 15 ° C, the reaction mixture was diluted with a mixture of ice and water ( 200 mL) and carefully adjusted to pH 9 -10 with solid potassium carbonate. The aqueous phase was extracted three times with dichloromethane and the combined organic phase was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residual oil was chromatographed on silica gel ( elution toluene - ethyl acetate 8 : 2 ) to give 3.54 g ( 73 percent yield ) of the title material as yellowish solid. HPLC (Method A): 0.9 min ( tailing ). HRMS (ESI) calcd for Ci0H12NO2 [M+H]+ m/z 178.0863, found 178.0882. 1H NMR (CDC13, 400 MHz) delta ppm: 7.40 (dd, J = 7.6, 1.5 Hz, 1H), 7.25 (d, J = 1.5 Hz, 1H), 7.12 (br. d, J = 7.6 Hz, 1H), 3.85 (s, 3H), 3.59 (t, J = 8.5 Hz, 2H), 3.05 (t, J = 8.5 Hz, 2H).
49%		A stirred solution of 2A (1 g, 5.7 mmol) in DCM (20 ml_) and TFA (10 mL) at -200C was treated with Et3SiH (10 mL). The reaction was warmed to RT slowly and stirred thereafter for 17 h. The reaction was quenched with 2 N NaOH until pH 8. The mixture was extracted with DCM (100 mL x 3). The combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. Chromatography (20percent EtOAc/hexanes) provided 2B (0.5g, 49percent).
24%	With sodium cyanoborohydride; acetic acid; at 30℃; for 16h;	To a solution of methyl IH-indole-6-carboxylate (5.0 g, 28.54 mmol) in AcOH (30 mL) wasadded NaBH3CN (5.4 g, 85.62 mmol). The mixture was stirred at 30 °C for 16 h. The reactionwas quenched with sat. aq. NaHCO3 (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether / EtOAc = 50 : I to 3 : I) to give the title compound (1.2 g, 24percent) as a whitesolid. ?H NMR (400 MHz, DMSO-d6) oe 7.16 (d, J7.6 Hz, IH), 7.14 (d, J=7.6 Hz, IH), 5.75 (s, IH), 3.78 (s, 3H), 3.52 (t,J 8.4 Hz, 2H), 2.95 (t,J 8.4 Hz, 2H).
	With sodium cyanoborohydride; acetic acid; at 0 - 15℃; for 2h;	Dissolve methyl indole-6-carboxylate (5.00 g, 28.5 mmol) in acetic acid (50 mL)In a 100 mL single-mouth bottle, sodium cyanoborohydride (8.85 g, 142 mmol) was slowly added at 0 °C.After completion, the reaction was carried out at 15 ° C for 2 hours. After the reaction is complete,The reaction solution was dried to dryness and then purified and evaporated with methylene chloride (200 mL).Extracted with dichloromethane (150 mL × 3),The combined organic phases were dried and concentrated to give the title compound.

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[3]ChemMedChem,2016,vol. 11,p. 2607 - 2620.
[4]Patent: WO2018/52903,2018,A1 .Location in patent: Page/Page column 22; 43-44.
[5]Patent: US2010/234340,2010,A1 .Location in patent: Page/Page column 20.
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2
[ 358-23-6 ]
[ 341988-36-1 ]
1-Trifluoromethanesulfonyl-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester [ No CAS ]