288385-99-9|1-(2-Fluoro-3-methoxy-6-nitrophenyl)propan-2-one| Ambeed

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Quality Control of [ 288385-99-9 ] Purity: 97% SDS Specification

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Product Details of [ 288385-99-9 ]

CAS No. :	288385-99-9
Formula :	C₁₀H₁₀FNO₄
M.W :	227.19
SMILES Code :	CC(CC1=C([N+]([O-])=O)C=CC(OC)=C1F)=O
MDL No. :	MFCD11977234
InChI Key :	VGDKNHRINLDMIS-UHFFFAOYSA-N
Pubchem ID :	22030743

Safety of [ 288385-99-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 288385-99-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	6
Fraction Csp3	0.3
Num. rotatable bonds	4
Num. H-bond acceptors	5.0
Num. H-bond donors	0.0
Molar Refractivity	56.49
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	72.12 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.81
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	1.44
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.29
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.	1.06
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	0.84
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.49

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.17
Solubility	1.54 mg/ml ; 0.00677 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.	-2.56
Solubility	0.626 mg/ml ; 0.00275 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	-2.93
Solubility	0.265 mg/ml ; 0.00117 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.	-6.66 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	0.0
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	2.0 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)	2.15

Application In Synthesis of [ 288385-99-9 ]

* 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 [ 288385-99-9 ]

[ 288385-99-9 ] Synthesis Path-Downstream 1~19

1
[ 121247-16-3 ]
[ 288385-99-9 ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium carbonate; In methanol; for 3h;Heating / reflux;	A mixture of 1-(2,3-difluoro-6-nitrophenyl) -propan-2-one (183 g) and potassium carbonate (100 g) in methanol (1L) was heated at reflux for 3 h. The reaction mixture was then cooled and concentrated in vacuo to remove most of the methanol. The residue was diluted with ethyl acetate (1L), filtered and washed with water. The separated aqueous layer was neutralized with 2N HCl and extracted with ethyl acetate (2x500 mL). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give a brown solid. The solid was triturated with diethyl ether and filtered to provide 1-(2-fluoro-3-methoxy-6-nitrophenyl)-propan-2-one (121 g, 71 %) as a yellow solid. LC/MS; (M+H)+ = 228.2

References: [1]Patent: WO2004/9542,2004,A2 .Location in patent: Page 34; 35.

2
[ 288385-99-9 ]
[ 649736-31-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	With pyridine hydrochloride; at 20 - 180℃; for 1.25h;Heating / reflux;	A mixture of 1-(2-fluoro-3-methoxy-6-nitrophenyl)-propan-2-one from previous step (454 mg, 21 mmol) and pyridinium chloride (0.9 g, 7.8 mmol) was stirred at 180 C for 75 min. The reaction was cooled to room temperature, diluted with 1N HCl (3mL) and ethyl acetate (10 mL) and filtered. The filtrate was washed with brine (2x), dried and concentrated in vacuo to give 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (410 mg, 96 %) as a grey solid, which was used without further purification for the next step. LC/MS; (M+H)+ = 214. 1H NMR (CDCl3): delta 2.37 (s, 3H), 4.22 (s, 2H), 6.95 (dd, 1H), 7.95 (d, 1H, J= 9.35 Hz)

References: [1]Patent: WO2004/9542,2004,A2 .Location in patent: Page 35.
[2]Organic Process Research and Development,2014,vol. 18,p. 89 - 102.

3
[ 288385-99-9 ]
aqueous ammonium acetate [ No CAS ]
[ 7705-07-9 ]
[ 288385-93-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	In water; acetone;	To a solution of <strong>[288385-99-9]3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene</strong> (11.36 g, 50 mmol) in acetone (200 ml) was added 4M aqueous ammonium acetate (700 ml) followed by a solution of titanium trichloride (15% in water, 340 ml) dropwise. The mixture was stirred for 10 minutes at ambient temperature and the mixture was extracted with ether. The organic layer was washed with 0.5N aqueous sodium hydroxide followed by water, brine, dried MgSO4) and the volatiles were removed under vacuum. The residue was purified by column chromatography eluding with methylene chloride to give 4-fluoro-5-methoxy-2-methylindole (8.15 g, 90%). 1H NMR Spectrum: (DMSO) 2.35 (s, 3H); 3.8 (s, 3H); 6.1 (s, 1H); 6.85 (dd, 1H); 7.02 (d, 1H)
90%	In water; acetone;	To a solution of <strong>[288385-99-9]3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene</strong> (11.36 g, 50 mmol) in acetone (200 ml) was added 4M aqueous ammonium acetate (700 ml) followed by a solution of titanium trichloride (15% in water, 340 ml) dropwise. The mixture was stirred for 10 minutes at ambient temperature and the mixture was extracted with ether. The organic layer was washed with 0.5N aqueous sodium hydroxide followed by water, brine, dried (MgSO4) and the volatiles were removed under vacuum. The residue was purified by column chromatography eluding with methylene chloride to give 4-fluoro-5-methoxy-2-methylindole (8.15 g, 90%). 1H NMR Spectrum: (DMSO) 2.35 (s, 3H); 3.8 (s, 3H); 6.1 (s, 1H); 6.85 (dd, 1H); 7.02 (d, 1H)

References: [1]Patent: US2003/199491,2003,A1 .
[2]Patent: US2003/212055,2003,A1 .

4
[ 288385-96-6 ]
[ 288385-99-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogenchloride; sodium methylate; sodium; In tetrahydrofuran; methanol;	A solution of sodium methoxide (freshly prepared from sodium (1.71 g) and methanol (35 ml)) was added to a solution of 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (16.2 g, 62 mmol), (prepared as described above), in methanol (200 ml) cooled at 5 C. The mixture was left to warm to ambient temperature and was stirred for 3 days. The volatiles were removed under vacuum and the residue was partitioned between ethyl acetate and 2N hydrochloric acid (1ml). The organic layer was concentrated to a total volume of 100 ml and THF (100 ml) and 6N hydrochloric acid (25 ml) were added. The mixture was stirred for 1 hour at ambient temperature. The volatiles were removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluding with ethyl acetate/petroleum ether (3/7) to give 3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene (12.7 g, 90%). MS-ESI: 250 [MNa]+ 1H NMR Spectrum: (CDCl3) 2.38 (s, 3H); 4.0 (s, 3H); 4.25 (s, 2H); 7.0 (dd, 1H); 8.05 (d, 1H)
90%	With hydrogenchloride; sodium methylate; sodium; In tetrahydrofuran; methanol;	A solution of sodium methoxide (freshly prepared from sodium (1.71 g) and methanol (35 ml)) was added to a solution of 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (16.2 g, 62 mmol), (prepared as described above), in methanol (200 ml) cooled at 5 C. The mixture was left to warm to ambient temperature and was stirred for 3 days. The volatiles were removed under vacuum and the residue was partitioned between ethyl acetate and 2N hydrochloric acid (1 ml). The organic layer was concentrated to a total volume of 100 ml and THF (100 ml) and 6N hydrochloric acid (25 ml) were added. The mixture was stirred for 1 hour at ambient temperature. The volatiles were removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluding with ethyl acetate/petroleum ether (3/7) to give 3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene (12.7 g, 90%). MS-ESI: 250 [MNa]+ 1H NMR Spectrum: (CDCl3) 2.38 (s, 3H); 4.0 (s, 3H); 4.25 (s, 2H); 7.0 (dd, 1H); 8.05 (d, 1H)
90%	With hydrogenchloride; sodium methylate; sodium; In tetrahydrofuran; methanol;	A solution of sodium methoxide (freshly prepared from sodium (1.71 g) and methanol (35 ml)) was added to a solution of 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (16.2 g, 62 mmol), (prepared as described above), in methanol (200 ml) cooled at 5 C. The mixture was left to warm to ambient temperature and was stirred for 3 days. The volatiles were removed under vacuum and the residue was partitioned between ethyl acetate and 2N hydrochloric acid (1 ml). The organic layer was concentrated to a total volume of 100 ml and THF (100 ml) and 6N hydrochloric acid (25 ml) were added. The mixture was stirred for 1 hour at ambient temperature. The volatiles were removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluding with ethyl acetate/petroleum ether (3/7) to give 3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene (12.7 g, 90%). MS-ESI: 250 [MNa]+ 1H NMR Spectrum: (CDCl3) 2.38 (s, 3H); 4.0 (s, 3H); 4.25 (s, 2H); 7.0 (dd, 1H); 8.05 (d, 1H)

References: [1]Patent: US2003/199491,2003,A1 .
[2]Patent: US2003/212055,2003,A1 .
[3]Patent: US2003/207878,2003,A1 .

5
[ 771-69-7 ]
[ 288385-99-9 ]

References: [1]Organic Process Research and Development,2014,vol. 18,p. 89 - 102.
[2]Patent: EP2940031,2015,A1 .

6
[ 67-56-1 ]
[ 121247-16-3 ]
[ 288385-99-9 ]

Yield	Reaction Conditions	Operation in experiment
		Step 3: preparation of 1-(2-fluoro-3-methoxy-6-nitrophenyl)propan-2-one In a 100mL round-bottomed flask 2g 1-(2,3-difluoro-6-nitrophenyl)propan-2-one prepared from Step 2 was added to a solution of sodium methoxide in methanol(40mL), wherein the solution of sodium methoxide in methanol was prepared by slowly adding 2.27g Na to methanol with sitrring in an ice bath and stirring for 1h at 50C after the addition. The mixture was reacted for 1h at room temperature before the reaction was complete, and quenched by adding 1mL water and extracted with dichloromethane. The organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound. 1H NMR(400MHz,DMSO-d6) delta ppm:8.04-8.07(m,1H),7.31-7.35(m,1H),4.20-4.21(d, 2H),3.98(s,3H),2.28(s,3H).

References: [1]Organic Process Research and Development,2014,vol. 18,p. 89 - 102.
[2]Patent: EP2940031,2015,A1 .Location in patent: Paragraph 0131.

7
[ 1022112-32-8 ]
[ 288385-99-9 ]

References: [1]Organic Process Research and Development,2014,vol. 18,p. 89 - 102.
[2]Patent: EP2940031,2015,A1 .

8
[ 288385-99-9 ]
[ 1609384-20-4 ]