500912-18-5|2-(2-Fluoro-6-methoxyphenyl)acetonitrile| Ambeed

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Quality Control of [ 500912-18-5 ] Purity: 95% SDS Specification

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Product Details of [ 500912-18-5 ]

CAS No. :	500912-18-5
Formula :	C₉H₈FNO
M.W :	165.16
SMILES Code :	COC1=CC=CC(F)=C1CC#N
MDL No. :	MFCD00671772
InChI Key :	IHTMDGUTWAQZBU-UHFFFAOYSA-N
Pubchem ID :	2779324

Safety of [ 500912-18-5 ]

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

Computational Chemistry of [ 500912-18-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.22
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	42.41
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	33.02 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.98
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	1.65
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.32
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.	1.86
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	2.55
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.07

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.14
Solubility	1.19 mg/ml ; 0.00722 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.	-1.96
Solubility	1.82 mg/ml ; 0.011 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	-3.29
Solubility	0.0855 mg/ml ; 0.000518 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.	-6.14 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)	1.5

Application In Synthesis of [ 500912-18-5 ]

* 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 [ 500912-18-5 ]

[ 500912-18-5 ] Synthesis Path-Downstream 1~34

1
[ 959163-01-0 ]
[ 500912-18-5 ]
[ 1588424-20-7 ]

Yield	Reaction Conditions	Operation in experiment
61%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;Inert atmosphere;	A mixture of 6-chloro-4-(ethyl amino) nicotinaldehyde (Scheme 1 compound 6) (1.7 g, 9.32 mmol), Scheme 56 compound 4 (2.0 g, 12.11 mmol) and K2C03 (3.8 g, 27.96 mmol) in dry DMF (10 mL) was heated to 100 C under nitrogen atmosphere for 16 h. After TLC showed the starting material was completely consumed, the reaction mixture was cooled to RT, diluted with EtOAc (2 x 50 mL), washed with water (2 x 20 mL) and brine (10 mL) then dried over Na2S04 and concentrated to give a residue which was purified by flash chromatography on silica gel (eluting with petroleum ether/EtOAc 100/0 gradually increasing to 60/40) to give 7-chloro-l-ethyl-3-(2-fluoro-6-methoxyphenyl)-l,6-naphthyridin-2(lH)- imine (800 mg, 26%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): delta 8.41 (s, 1H), 7.51 (q, J= 8.0 Hz, 1H), 7.41 (d, J= 10.6 Hz, 2H), 7.07-6.92 (m, 2H), 4.26 (m, 2H), 3.77 (d, J = 2.4 Hz, 3H), 1.22-1.16 (m, 3H). MS [ESI, MH+] = 332.09.

References: [1]Patent: WO2014/52365,2014,A1 .Location in patent: Page/Page column 299-300.

2
[ 773837-37-9 ]
[ 146137-74-8 ]
[ 500912-18-5 ]

Yield	Reaction Conditions	Operation in experiment
46%	In ethanol; at 80℃; for 4h;	To a solution of Scheme 56 compound 3 (5.7 g, 26.15 mmol) in dry EtOH (70 mL) was added NaCN (1.4 g, 28.76 mmol) and the reaction mixture was stirred at 80 C for 4 h. After TLC showed the starting material was completely consumed, the reaction mixture was concentrated to give a crude compound which was diluted with ice water (30 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated to give a residue which was purified by column chromatography (eluting with petroleum ether/EtOAc 100/0 gradually increasing to 60/40) to give Scheme 56 compound 4 (2.0 g, 46%) as a colorless liquid. MS [ESI, MH+] = 166.06.

References: [1]Patent: WO2014/52365,2014,A1 .Location in patent: Page/Page column 299-300.

3
2-fluoro-6-methoxybenzyl alcohol [ No CAS ]
[ 500912-18-5 ]

References: [1]Patent: WO2014/52365,2014,A1 .

4
[ 137654-21-8 ]
[ 500912-18-5 ]

References: [1]Patent: WO2014/52365,2014,A1 .

5
[ 500912-18-5 ]
[ 1588423-04-4 ]

References: [1]Patent: WO2014/52365,2014,A1 .

6
[ 500912-18-5 ]
[ 1588424-21-8 ]

References: [1]Patent: WO2014/52365,2014,A1 .

7
[ 500912-18-5 ]
[ 1588424-24-1 ]

References: [1]Patent: WO2014/52365,2014,A1 .

8
[ 500912-18-5 ]
1'-benzyl-4-fluoro-2H-spiro[benzofuran-3,4'-piperidine]-2-one hydrobromide [ No CAS ]

References: [1]Patent: EP3480198,2019,A1 .

9
[ 500912-18-5 ]
[ 10429-82-0 ]
1-benzyl-4-(2-fluoro-6-methoxyphenyl)piperidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
132 mg		First, sodium bis(trimethylsilyl) amide (1.0 M tetrahydrofuran solution) (1.6 mL) was added dropwise to a solution of <strong>[500912-18-5]2-<strong>[500912-18-5](2-fluoro-6-methoxyphenyl)acetonitrile</strong></strong> (86 mg) in tetrahydrofuran (2.4 mL) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. N-benzyl-bis(2-chloroethyl)amine hydrochloride (140 mg) was added to the resultant solution, followed by reflux for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then was dried with anhydrous magnesium sulfate. the solvent was removed by evaporation under reduced pressure. The obtained residue was purified by silica gel column chromatography (diethylether/n-hexane = 50/50) to obtain 1-benzyl-4-(2-fluoro-6-methoxyphenyl)piperidine-4-carbonitr ile (132 mg). 1H-NMR (400MHz, CDCl3) delta: 2.28-2.37(m,2H),2.43-2.50(m,2H),2.50-2.59(m,2H),2.89-2.98(m ,2H),3.58(s,2H),3.91(s,3H),6.67(ddd,J=12.9,8.4,1.2Hz,1H),6. 74(d,J=8.3Hz,1H),7.21-7.29(m,3H),7.29-7.36(m,4H).

References: [1]Patent: EP3480198,2019,A1 .Location in patent: Paragraph 0225; 0226.

10
[ 24424-99-5 ]
[ 500912-18-5 ]
(+/-)-tert-butyl cyano(2-fluoro-6-methoxyphenyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10.4 g		[0473] Under argon and at -65C., a 2 M solution of LDA in THF (23 ml, 45 mmol) was added slowly to a solution of <strong>[500912-18-5](2-fluoro-6-methoxyphenyl)acetonitrile</strong> (5.00 g, 30.3 mmol, CAS-RN 500912-18-5) in THF (25 ml), and the mixture was allowed to warm to 0C. and, after 15 min, once more cooled to -65C. Subsequently, a solution of di-tert-butyl dicarbonate (10 ml, 45 mmol) in THF (11 ml) was slowly added dropwise, keeping the internal temperature below -40C. The mixture was stirred overnight, with the temperature gradually rising to RT. With ice cooling and stirring, 1 M hydrochloric acid (45.4 ml, 45.4 mmol) was then slowly added to the mixture, followed by water (30 ml) and ethyl acetate (80 ml). After agitation and phase separation, the aqueous phase was extracted once with ethyl acetate (80 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was taken up in dichloromethane and purified by flash column chromatography (500 g of silica gel, cyclohexane/ethyl acetate 10:1). The combined target fractions were concentrated, and the residue was dried under reduced pressure. This gave 10.4 g (62% purity, 80% of theory) of the title compound. [0474] LC-MS (Method 1): Rt=1.89 min; MS (ESIpos): m/z=266 [M+H]+

References: [1]Patent: US2020/31775,2020,A1 .Location in patent: Paragraph 0472-0474.

11
[ 5292-43-3 ]
[ 500912-18-5 ]
(+/-)-tert-butyl 3-cyano-3-(2-fluoro-6-methoxyphenyl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11.4 g		[0549] To a solution of <strong>[500912-18-5](2-fluoro-6-methoxyphenyl)acetonitrile</strong> (5.00 g, 30.3 mmol) in THF (50 ml) under argon was added gradually while stirring, at -78 to -60C., a 2 M solution of LDA in THF (23 ml, 45 mmol). The mixture was allowed to come to 0C. and, after 15 min, cooled back down again to -78C. Subsequently, tert-butyl bromoacetate (6.7 ml, 45 mmol) was slowly added dropwise thereto at -78 to -60C. while stirring. The cooling bath was removed and, with stirring, the mixture was allowed to slowly warm to RT. After 4 h, at 0C., water and ethyl acetate (50 ml each) were added, the mixture was agitated and the phases were separated. The aqueous phase was extracted once with ethyl acetate (50 ml). The combined organic phases were washed once with saturated aqueous sodium chloride solution (100 ml), dried over sodium sulfate, filtered and concentrated, and the residue was dried under reduced pressure. This gave 11.4 g (93% purity, 100% of theory, comprises further impurities) of the title compound. [0550] LC-MS (Method 1): Rt=2.00 min; MS (ESIpos): m/z=280 [M+H]+ [0551] 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.334 (16.00), 1.397 (0.78), 1.425 (3.42), 2.844 (0.47), 2.862 (0.47), 2.999 (0.42), 3.020 (0.42), 3.309 (3.17), 4.017 (0.76), 4.635 (0.44), 6.894 (0.43), 6.958 (0.53), 6.980 (0.58), 7.402 (0.46), 7.419 (0.45). [0552] 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=7.41 (dd, 1H), 6.97 (d, 1H), 6.89 (t, 1H), 4.63 (dd, 1H), 3.89 (s, 3H), 3.03 (dd, 1H), 2.83 (dd, 1H), 1.33 (s,9H).

References: [1]Patent: US2020/31775,2020,A1 .Location in patent: Paragraph 0548-0552.

12
[ 500912-18-5 ]
[ 74-88-4 ]
(+/-)-2-(2-fluoro-6-methoxyphenyl)propanenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%		[0428] Under argon and at -78C., a mixture of 2.5 M butyllithium solution in hexane (13 ml, 33 mmol) and THF (50 ml) was added slowly to a solution of N,N-diisopropylethylamine (5.8 ml, 33 mmol) in THF (75 ml). The reaction mixture was allowed to warm to 0C., stirred at 0C. for 5 min and cooled back down again to -78C. A solution of <strong>[500912-18-5](2-fluoro-6-methoxyphenyl)acetonitrile</strong> (5.00 g, 30.3 mmol, CAS-RN 500912-18-5, commercially available) in THF (25 ml) was then added slowly. The reaction mixture was once more allowed to warm to 0C., stirred at 0C. for 5 min and cooled back down again to -78C. A solution of iodomethane (2.0 ml, 31.79 mmol) in THF (25 ml) was then added slowly. The mixture was stirred overnight, with the temperature gradually rising to RT. At 0C., saturated ammonium chloride solution and water (50 ml each) were then added and the mixture was shaken and extracted twice with ethyl acetate (150 ml each). The combined organic phases were washed once with saturated aqueous sodium chloride solution (200 ml), dried over sodium sulfate, filtered and concentrated, and the residue was taken up in dichloromethane and purified by flash column chromatography (400 g of silica gel Buchi Snap-Cartridge KP-Sil, cyclohexane/ ethyl acetate 9:1). The combined target fractions were concentrated, and the residue was (briefly) dried under reduced pressure. This gave 3.33 g (100% purity, 61% of theory) of the title compound. [0429] GC-MS (Method 12): Rt=4.31 min; MS (ESIpos): m/z=179 [M]+ [0430] 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.492 (15.85), 1.509 (16.00), 3.314 (9.13), 3.887 (0.90), 4.452 (0.69), 4.455 (0.70), 4.470 (2.12), 4.473 (2.10), 4.488 (2.11), 4.491 (2.05), 4.505 (0.69), 4.508 (0.65), 6.861 (1.62), 6.863 (1.60), 6.884 (2.45), 6.907 (1.81), 6.909 (1.81), 6.943 (3.36), 6.964 (3.72), 7.353 (1.56), 7.370 (1.87), 7.374 (2.99), 7.391 (3.02), 7.395 (1.60), 7.412 (1.36). [0431] 1H-NMR (400 MHz, DMSO-d6): 5 [ppm]=7.44-7.30 (m, 1H), 6.95 (d, 1H), 6.92-6.85 (m, 1H), 4.48 (qd, 1H), 3.88 (s, 3H), 1.50 (d,3H).

References: [1]Patent: US2020/31775,2020,A1 .Location in patent: Paragraph 0427-0431.

13
[ 500912-18-5 ]
(+/-)-4-[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(2-fluoro-6-methoxyphenyl)butanoic acid [ No CAS ]